Select a psychoactive drug that is of pharmacological interest to you, but not one you will review as part of your Critical Review. For this paper, you may choose drugs of abuse; however, the paper mu

Drugs 2008; 68 (5): 653-689 ADIS D RUG EVALUATION 0012-6667/08/0005-0653/$53.45/0 © 2008 Adis Data Information BV. All rights reserved. Bupropion A Review of its Use in the Management of Major Depressive Disorder Sohita Dhillon, Lily P.H. Yang and Monique P. Curran Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA Various sections of the manuscript reviewed by:

I.M. Anderson, Neuroscience and Psychiatry Unit, University of Manchester, Manchester, England; P. Bech, Psychiatric Research Unit, Frederiksborg General Hospital, Hillerød, Denmark; P. Casey, Department of Psychiatry, Mater Misericordiae University Hospital, Dublin, Ireland; P. Cowen, University Department of Psychiatry, Warneford Hospital, Oxford, England; S. Curran, Calder Unit, Fieldhead Hospital, Wakefield, England; J.M. Donoghue, Medicines in Mental Health Ltd., Liverpool, England; M.H. Lader, Institute of Psychiatry, King’s College, London, England.

Data Selection Sources: Medical literature published in any language since 1980 on ‘bupropion’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE or AdisBase search terms were ‘bupropion’ and (‘depression’ or ‘depressive disorder’ or ‘antidepressant’). Searches were last updated 12 March 2008.

Selection: Studies in patients with major depressive disorder who received bupropion. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Bupropion, major depressive disorder, antidepressant, dopamine and norepinephrine reuptake inhibitor, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents Summary...................................................................................654 1. Introduction............................................................................. 657 2. Pharmacodynamic Properties............................................................. 658 3. Pharmacokinetic Properties...............................................................659 3.1 Absorption and Distribution...........................................................659 3.2 Metabolism and Elimination...........................................................660 3.3 Special Patient Populations...........................................................660 3.4 Pharmacokinetic Drug Interactions.................................................... 660 4. Therapeutic Efficacy.....................................................................661 4.1 Efficacy of Bupropion Immediate Release.............................................. 662 4.1.1 Comparisons with Placebo......................................................664 4.1.2 Comparisons with Other Antidepressants......................................... 664 4.2 Efficacy of Bupropion Sustained Release (SR)...........................................664 4.2.1 Comparisons with Placebo......................................................664 4.2.2 Comparisons with Selective Serotonin Reuptake Inhibitors (SSRIs)....................666 4.2.3 Efficacy in Patients with Prior Citalopram Therapy.................................667 4.3 Efficacy of Bupropion Extended/Modified Release (XR)..................................668 4.3.1 Comparisons with Placebo......................................................670 4.3.2 Comparisons with Escitalopram..................................................672 654Dhillon et al. 4.3.3 Comparisons with Venlafaxine Extended Release.................................672 4.4 Meta-Analyses....................................................................... 672 5. Tolerability...............................................................................673 5.1 General Profile......................................................................673 5.2 Serious Adverse Events...............................................................675 5.2.1 Seizures....................................................................... 675 5.2.2 Suicide........................................................................ 676 5.3 Comparisons with Other Antidepressants............................................... 676 5.3.1 Versus Tricyclic Antidepressants..................................................676 5.3.2 Versus an Atypical Antidepressant............................................... 676 5.3.3 Versus SSRIs and a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)..............676 5.3.4 In Patients with Prior Citalopram Therapy......................................... 677 5.4 Sexual Functioning................................................................... 677 5.4.1 Comparisons with Placebo......................................................678 5.4.2 Comparisons with SSRIs and an SNRI.............................................680 5.5 Bodyweight.........................................................................680 5.6 Cardiovascular Events................................................................681 6. Dosage and Administration...............................................................681 7. Place of Bupropion in the Management of Major Depressive Disorder.........................682 Summary Bupropion is presumed to be a dopamine-norepinephrine reuptake inhibitor and is Abstract an effective antidepressant. It is available as three oral formulations: (i) bupropion immediate release (IR) [Wellbutrin ®] administered three times daily; (ii) bupro- pion 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 bupro- pion 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, bupro- pion 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 dysfunc- tion 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 adminis- tration. © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review655 As with all antidepressants, the precise mechanism of action of bupropion in Pharmacological MDD is unknown, although bupropion selectively inhibits dopamine and nore- Properties pinephrine reuptake. The reuptake inhibition potential of bupropion is greater for dopamine than for norepinephrine. Importantly, bupropion does not affect sero- tonergic pathways and does not act on postsynaptic histamine, α- or β-adrenergic, dopamine or acetylcholine receptors.

Time to reach maximum plasma concentration (C max ) varied between bupro- pion 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 C max 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 (t 1/2) of 20–21 hours and is predominantly (87%) excreted in the urine as metabolites. The t 1/2 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. Three-times-daily bupropion IR was effective in the treatment of MDD in a 6- Therapeutic Efficacy 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 prevent- ing relapse in one 52-week relapse-prevention study in a similar patient popula- tion. 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 © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 656Dhillon et al. self-rated Inventory of Depressive Symptomology scale or Montgomery- Asberg 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. Additional- ly, 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).

All three formulations of bupropion (IR, SR or XR) were generally well tolerated Tolerability 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 recommen- ded 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 escitalo- pram) and an SNRI (venlafaxine XR) in patients with moderate to severe MDD, some adverse events were reported in fewer bupropion than comparator recipi- ents. © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review657 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. 1. IntroductionCurrently available pharmacological options of generally similar antidepressant efficacy include the first-generation drugs, such as tricyclic antidepres- According to the Diagnostic and Statistical Man- sants (TCAs) [e.g. nortriptyline and doxepin] and ual of Mental Disorders (DSM) criteria, major de- monoamine oxidase inhibitors (MAOIs) [e.g.

pressive disorder (MDD) is characterized by at least phenelzine], and the second-generation drugs, such one major depressive episode (defined as at least as selective serotonin reuptake inhibitors (SSRIs) 2 weeks of depressed mood or loss of interest ac- [e.g. citalopram, sertraline and paroxetine] and sero- companied by at least four additional symptoms of tonin and norepinephrine reuptake inhibitors depression, including changes in sleep, appetite or (SNRIs) [e.g. venlafaxine extended release (XR)]. [5] weight, and psychomotor activity). [1] MDD is one of Most first-generation drugs act at several sites in the the most common psychiatric conditions worldwide brain that may or may not affect depression, whereas and is associated with considerable morbidity and the second-generation drugs have been designed to mortality. [2,3] The life-time and 12-month preva- act at one or more specific neurotransmitter receptor lences of MDD in Europe in the year 2000 were sites that are implicated in depression. [6] 13% and 4%; [4] in the US in 2002, the corresponding prevalence values were 16% and 7%. [3] Fortunately, Bupropion (Wellbutrin ®, Wellbutrin SR ®, MDD is a treatable condition, with a number of Wellbutrin XL ®, Wellbutrin XR ®)1, a second gener- therapeutic options available, including pharmaco- ation antidepressant (a presumed dopamine and nor- therapy, psychotherapy and electroconvulsive ther- epinephrine reuptake inhibitor), is approved in the apy. [2] However, a large number of patients do not US [7-9] and some European countries [10] for the treat- respond well to therapy; ≈50% of patients may ment of MDD, although there are differences in the continue to experience some residual symptoms of approval status of formulations between various depression after antidepressant therapy and up to markets. The drug is available as three oral formula- 20% of patients may show minimal or no response tions: (i) bupropion immediate release (IR) [Wellbu- to therapy. [2] Furthermore, in patients who do res- trin ®]][7] administered three times daily; (ii) bupro- pond to therapy, relapse is a common occurrence. [2] pion sustained release (SR) [Wellbutrin SR ®]][7] 1The use of trade names is for product identification purposes only and does not imply endorsement.

© 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 658Dhillon et al.

Table I. Overview of the pharmacodynamic properties of bupropion Mechanism of action Weak inhibitor of dopamine reuptake (IC 50 550 nmol/L) [17] Weak inhibitor of norepinephrine reuptake (IC 50 1900 nmol/L) [17] Noncompetitive inhibitor of nicotinic acetylcholine receptors (IC 50 1.8–14 µmol/L) [17,18] No significant direct effects on serotonin neurotransmission [11] No effect on monoamine oxidase [11] Does not bind to postsynaptic receptors (including histamine, α- or β-adrenergic, serotonin, dopamine, or acetylcholine receptors) [11] Effects relating to enhanced dopaminergic and noradrenergic function Antidepressant activity (section 4) Resolution of sleepiness and fatigue [19] Anti-craving and anti-withdrawal effects [20] May be associated with weight loss [12] (increased incidence relative to TCAs; see section 5.5) No serotonergic effects Minimal effect on sexual functioning (section 5.4) Less weight gain relative to TCAs (section 5.5) No antihistaminergic effects Less weight gain relative to TCAs (section 5.5) Less sedation or drowsiness relative to TCAs and escitalopram (section 5) Cardiovascular effects Hypertension in some patients, including those receiving concomitant administration of a nicotine patch [7-10] (section 5.6) No clinically significant effect on QTcF in healthy volunteers [10] Other effects Lengthened REM latency in two [21,22] and increased REM sleep in two [21,23] of three studies [21-23] Decreases tumour necrosis factor levels [24-29] No teratogenic effects in a clinical study; a however, increased teratogenic effects were observed in an animal study [7-9] a In a retrospective study in 1213 of 7005 infants with in utero exposure to bupropion. [30] IC50 = concentration required for 50% inhibition in vitro; QTcF = QT interval corrected using Fridericia’s formula; REM = rapid eye movement; TCAs = tricyclic antidepressants. administered twice daily; and (iii) bupropion slow Bupropion (amfebutamone) is an aminoketone release formulations (bupropion extended release with structural similarity to diethylpropion (am- [Wellbutrin XL ®][7] available in the US and bupro- fepramone) and phenylethylamines. [7-9] The precise pion modified release [Wellbutrin XR ®][10] avail- mechanism of action of bupropion, as with all anti- able in some countries in Europe [both are referred depressants, is unknown. [7-10] However, the pre- to as bupropion XR hereafter]) administered once sumed mechanism of action of bupropion is selec- daily. In addition, bupropion SR (Zyban ®]) is ap- tive inhibition of norepinephrine and dopamine proved as an aid for smoking cessation in the US and reuptake; bupropion is a more potent inhibitor of most European countries, whereas bupropion XR is dopamine reuptake than of norepinephrine reuptake also approved for seasonal affective disorder in the (table I).

US. This review examines the pharmacological Concentrations of bupropion in the brain re- properties, clinical efficacy and tolerability of all mained above the 50% inhibitory concentration for three formulations of bupropion in adult and elderly inhibition of dopamine and norepinephrine uptake patients with MDD (non-bipolar depression).

over a 12-hour administration interval of bupropion SR. [12] Positron emission tomography or single pho- 2. Pharmacodynamic Properties ton emission computed tomography studies in pa- tients with depression [14,15] or in healthy volun- The pharmacodynamic properties of bupropion teers [14,16] showed that the mean occupancy of the have been reviewed extensively; [11-13] hence, only a human dopamine transporter by bupropion SR and brief summary focusing on clinical data is provided here (see also table I). its metabolites was 14% [14] and 21% [15] at steady © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review659 state, and was 26% [16] at 3 hours after dose adminis- formulation (three). [11] Steady state was reached for tration. all formulations within 8 days. [7-10] Bupropion had no effect on the release or trans- Although the C max of bupropion was ≈15% low- port of other neurotransmitters (including serotonin er after administration of the SR compared with the and histamine) and does not bind to the postsynaptic IR formulation, equivalence between the two formu- receptors of other neurotransmitters (table I). There- lations was established for C max and area under fore, bupropion is less frequently associated with the concentration-time curve (AUC). [8] Bioequiva- some adverse events common in patients treated lence was met if the same parameter of each formu- with TCAs or SSRIs (e.g. sexual dysfunction, lation was within the 90% CI of 0.80 to 1.25. [31] In weight gain or sedation; discussed in section 5).

addition, there was equivalence between these two formulations for the C max and AUC of its three pharmacologically active metabolites (hydrox- 3. Pharmacokinetic Properties ybupropion, threohydrobupropion and erythrohy- The pharmacokinetic data pertaining to bupro- drobupropion). Similarly, equivalence was estab- pion therapy in adults discussed in this section are lished for C max and AUC of bupropion and its based on European [10] and US [7-9] prescribing infor- metabolites in a study comparing the XR formula- mations, the Netherlands’ Public Assessment Re- tion with the IR formulation and in a study compar- port, [31] studies [32-39] and reviews. [11,40,41] Bupropion ing the XR formulation with the SR formulation. [9] is a racemic mixture; the pharmacokinetics of the In 34 healthy volunteers given multiple doses of individual enantiomers have not been studied. [7-9] bupropion SR 150 mg twice daily, C max and AUC values of the active metabolites were generally 3.1 Absorption and Distribution greater than that of bupropion (1262 ng/mL and 25 023 ng •h/mL for hydroxybupropion, 679 ng/ Bupropion IR is rapidly absorbed with median mL and 13 483 ng •h/mL for threohydrobupropion time (t max ) to reach maximum plasma concentra- and 137 ng/mL and 2727 ng •h/mL for erythrohy- tions (C max ) of ≈2 hours (table II). T max for the SR drobupropion). [32] and XR formulations of bupropion were ≈3 and The AUC and C max of bupropion, hydroxybupro- ≈5 hours (table II). Moreover, the SR and XR for- pion and threohydrobupropion increased propor- mulations of bupropion were associated with fewer tionally with increasing dose after a single dose of daily exposures to C max (two and one) than the IR 50–200 mg and after multiple doses of 300–450 mg/ day. [10] The presence of food did not significantly affect the absorption of bupropion XR; [10] food had a small effect on the C max but not the AUC of bupro- pion SR. [8] Absolute bioavailability has not been determined for bupropion [10] as no intravenous formulation is available, [40] although at least 87% of an adminis- tered dose is absorbed. [10] Bupropion’s active metabolites accumulate and reach steady-state concentrations higher than those of bupropion. [7-10] Although in vivo animal studies indicate reduced potency of these metabolites rela- tive to bupropion, the metabolites have higher sys- temic exposure than that of bupropion and as such may be of clinical importance.

The apparent volume of distribution of bupropion is ≈2000 L [10] and its plasma protein binding is 84%. [7-9] Bupropion and its active metabolites cross Table II. Pharmacokinetics of bupropion (BUP) at steady state.

Data were obtained from two randomized, open-label, crossover trials in 99 healthy volunteers [32,34] that compared BUP extended release (XR) or BUP sustained release (SR) with BUP immediate release (IR). [41] The three formulations of BUP were administered orally within the approved dosage range (BUP XR 300 mg once daily, BUP SR 150 mg twice daily or BUP IR 100 mg three times daily) Regimen t max (h) a Cmax Cmin AUC 24 (ng/mL) (ng/mL) (ng •h/mL) BUP IR≈2.0 160, b 168 c27,b 32 c 1744, b 1731 c BUP SR≈3.0 136 29 1718 BUP XR≈5.0 161 26 1545 a As reported in the US manufacturer’s prescribing information for bupropion IR, SR and XR. [7-9] b In study comparing BUP SR vs BUP IR.

c In study comparing BUP XR vs BUP IR.

AUC 24 = area under the plasma concentration-time curve from time 0 to 24 h; C max = maximum plasma concentration; C min = minimum plasma concentration; t max = time to C max . © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 660Dhillon et al.

the blood-brain barrier and the placenta, and are by ≈2.5-fold for threohydrobupropion and er- present in human breast milk. [10] In CSF, as with ythrohydrobupropion), t max was longer (by plasma, the concentrations of the active metabolites≈20 hours for all three metabolites) and t 1/2 was are much greater than that of bupropion; the CSF longer (by ≈5-fold for hydroxybupropion and by ≈2- concentrations of these metabolites, but not of fold for threohydrobupropion and erythrohy- bupropion, are strongly correlated to plasma con- drobupropion). As a result, bupropion is contraindi- centrations (r = 0.82–0.94 vs r = 0.47). [33] cated (in some European countries) or should be used with extreme caution (in the US) in patients 3.2 Metabolism and Elimination with severe hepatic cirrhosis (section 6).

Limited data are available regarding the pharma- Bupropion is extensively metabolized in the liver cokinetics of bupropion in patients with renal im- to its metabolites, and minimal proportions of un- pairment. [7-10] An inter-study comparison of the changed drug are expected to reach the systemic pharmacokinetic parameters of bupropion in pa- circulation. [7-10] Bupropion is metabolized mainly by tients with end-stage renal disease with those in cytochrome P450 (CYP) 2B6 isoenzyme to hydrox- normal volunteers demonstrated that the C max and ybupropion. Threohydrobupropion and erythrohy- AUC of bupropion were similar in the two patient drobupropion formation involves carbonyl reduc- population. However, there was a 2.3- and 2.8-fold tion of bupropion, and does not involve CYP iso- increase in the AUC of hydroxybupropion and thre- enzymes.

ohydrobupropion in patients with renal failure.

The mean elimination half-life (t 1/2) of bupropion Pharmacokinetic data from elderly patients are is 20–21 hours. [7-10] Hydroxybupropion also has a inconsistent. A single-dose study did not report mean t 1/2 of ≈20 hours, but threohydrobupropion and pharmacokinetic differences for bupropion or its erythrohydrobupropion have longer t 1/2 values of active metabolites in elderly patients compared with ≈33 and ≈37 hours, respectively. After an oral dose younger adult patients; [7-9] another single- and multi- of 14C-bupropion, radioactivity was recovered, pre- ple-dose study indicated that greater accumulation dominantly as metabolites (only 0.5% as unchanged of bupropion and its metabolites was possible in drug), mostly in the urine (87%) and to a lesser elderly patients. [10,35] extent in the faeces (10%).

Gender, smoking or left ventricular dysfunction did not affect the pharmacokinetics of bupropion. [7- 3.3 Special Patient Populations 10] CYP2B6 or CYP2D6 phenotype may have some Although no statistically significant differences influence on the metabolism of bupropion. [36,37] in the pharmacokinetics of bupropion and its active metabolites were observed in patients with mild to 3.4 Pharmacokinetic Drug Interactions moderate hepatic cirrhosis compared with healthy volunteers, increased individual variability was re- Since bupropion is metabolized by CYP2B6, co- ported. [7-10] Therefore, caution is advised and the administration of bupropion and drugs that affect recommended bupropion dose is reduced in patients CYP2B6 isoenzyme activity may alter the plasma with mild to moderate hepatic impairment (section concentrations of bupropion and hydroxybupropion 6). In patients with severe cirrhosis, systemic expo- (see table III for a summary of potential interactions sure to bupropion was substantially increased (C max , between bupropion and other drugs).

AUC and t 1/2 increased by ≈70%, 3-fold and ≈40%, respectively, compared with healthy volun- As bupropion is extensively metabolized, caution teers). [7-10] C max values of all three active metabo- is advised when bupropion is coadministered with lites were lower in patients with severe hepatic drugs that induce or inhibit its metabolism. [10] For cirrhosis than in healthy volunteers (by ≈70% for example, in healthy volunteers, repeated administra- hydroxybupropion and by ≈30% for threohy- tion (20 days) of ritonavir 600 mg twice daily de- drobupropion and erythrohydrobupropion); AUC creased bupropion C max by ≈60% and AUC by was higher (by ≈1.5-fold for hydroxybupropion and≈65%. The plasma concentrations of bupropion’s © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review661 Table III. Potential pharmacokinetic interactions between bupropion (BUP) and other drugs [7-10,38,39,41] Drug interaction category Example Potential interaction CYP2B6 substrates Cyclophosphamide, ifosfamide↑ Bupropion levels and ↓ hydroxybupropion levels CYP2B6 inhibitors Clopidogrel, orphenadrine,↑ Bupropion levels and ↓ hydroxybupropion levels ticlopidine Agents metabolized by Antidepressants (e.g. nortriptyline,↑ Levels of the concomitantly administered agent CYP2D6 imipramine, desipramine, paroxetine, fluoxetine, sertraline, citalopram) Antipsychotics (e.g. haloperidol,↑ Levels of the concomitantly administered agent risperidone, thioridazine) β-Blockers (e.g. metoprolol)↑ Levels of the concomitantly administered agent Type 1C antiarrhythmics (e.g.↑ Levels of the concomitantly administered agent propafenone, flecainide) Venlafaxine↑ Plasma concentrations of venlafaxine and its metabolite O-desmethylvenlafaxine Inducers of metabolism Carbamazepine, phenytoin↓ Bupropion levels and ↑ hydroxybupropion levels Agents metabolized by Lamotrigine Bupropion did not significantly effect the pharmacokinetics of lamotrigine glucuronidation Other agents Alcohol No pharmacokinetic interaction Diazepam No in vitro basis for a pharmacokinetic interaction, although less sedation was observed in healthy volunteers given concomitant BUP and diazepam than in those given diazepam alone Monoamine oxidase inhibitors↑ Enhancement of catecholaminergic pathways via a separate mechanism to BUP Ritonavir, lopinavir/ritonavir May ↓ levels of bupropion and its active metabolites (see section 3.4) CYP = cytochrome P450; ↑ indicates increase; ↓ indicates decrease.

active metabolites were also decreased. Short-term There is limited information regarding the con- comitant administration of bupropion with levodo- (200 mg twice daily for 2 days) administration of pa, amantadine or alcohol. [10] However, because of ritonavir did not significantly affect bupropion met- an increase in the incidence of adverse events with abolism. [10] concomitant levodopa or amantadine (nausea, vom- Bupropion and hydroxybupropion both inhibit iting, neuropsychiatric events), caution is recom- CYP2D6; caution is recommended for concomitant mended. [7-10] Similarly, as neuropsychiatric adverse administration of bupropion with other medications events or reduced alcohol tolerance have been asso- that are metabolized by CYP2D6, and a decrease in ciated with concomitant alcohol consumption, it dosage of the concomitant drug may need to be should be minimized or reduced during bupropion considered. [7-10] In healthy volunteers who were ex- treatment. [7-10] tensive CYP2D6 metabolizers, coadministration of bupropion and desipramine increased C max and 4. Therapeutic Efficacy AUC of despiramine by 2- to 5-fold, and the inhibi- tive effect of bupropion on CYP2D6 persisted for at The efficacy of oral bupropion three times daily least 7 days after the last dose of bupropion.

[10] (bupropion IR) or twice daily (bupropion SR) has An increased incidence of adverse events may been reviewed previously. [42,43] This section briefly result from concomitant administration of bupro- discusses the efficacy of bupropion IR (section 4.1) pion with MAOIs, as MAOIs also enhance catecho- and bupropion SR (section 4.2) in the treatment of laminergic pathways (albeit via a different mecha- MDD, with the focus being on data from larger nism to that of bupropion). [10] Therefore, the con- (n >100 patients for bupropion IR and >200 patients comitant use of these medications is for bupropion SR), fully published trials. Also dis- contraindicated. [7-10] cussed is the efficacy of the once-daily oral formula- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 662Dhillon et al.

tion of bupropion XR in patients with MDD (section as several parameters assessing health related-quali- 4.3), some data for which are currently available ty of life (HR-QOL).

only as abstracts and posters. [44,45] Also measured were the response rates (defined as ≥50% reduction from baseline in IDS-IVR-30, [57] Eligible patients had a primary diagnosis of MADRS, [45] HAM-D [45,47,48,52-56,58-60] or QIDS- nonpsychotic, moderate to severe MDD based on SR-16 [62,63] total scores), CGI-I response rates (de- the DSM-III, [46] DSM-III-R [47-50] or DSM-IV [45,51-59] fined as the proportion of patients with a CGI-I score criteria, with the duration of the current episode of 1 [‘much’ improved] or 2 [‘very much’ im- being ≥4, [46-51,60,61] ≥8 [52-56,59] or ≥12 [57,58] weeks to proved]) [45,47,48,52,53,55,56,58,60,61] and the remission ≤2 years; in one study the diagnosis of MDD was rates (defined as the proportion of patients with a based on criteria of Feighner et al. [61] final IDS-IVR-30 score ≤15, [57] a HAM-D total Most studies excluded patients with a history of score ≤7, [58,59] a MADRS total score of ≤11 [45] or attempted suicide or active suicidality, a known <8 [53] or a QIDS-SR-16 score of ≤5 at study predisposition to seizures or those who were receiv- end[62,63] ).

ing medications that lowered the threshold of Most efficacy assessments were based on the seizures, a history or current diagnosis of other intent-to-treat population (ITT) and used last-obser- psychiatric disorders (including bipolar depression), vation-carried-forward (LOCF) analysis. Analysis or those who were receiving psychoactive drug ther- for primary and secondary variables used analysis of apy within 1–2 weeks of randomization (2 weeks for covariance (ANCOVA) unless specified otherwise.

MAOIs or protriptyline, and 4 weeks for fluoxetine There were no between-group differences in terms or investigational drugs).

of demographic and disease activity/health status Where specified, the primary efficacy measures characteristics at baseline within each individual were the changes from baseline in the 21-item Ham- trial unless specified otherwise.

ilton Rating Scale for Depression (HAM-D), [47] the 30-item self-rated Inventory of Depressive 4.1 Efficacy of Bupropion Symptomology scale (IDS-IVR-30), [57] the Mont- Immediate Release gomery- Asberg Depression Rating Scale (MADRS) [44,45] and the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total scores, [58] The efficacy of oral bupropion IR three times the time to depression relapse (defined as the time daily was evaluated in several 6- to 13-week, ran- from randomization for double-blind therapy to the domized, double-blind, single-, [61] or multicen- first prescription of pharmacotherapy or electrocon- tre [46-48,50,60] trials in outpatients (aged vulsive therapy), [56] and remission of disease (de- ≥18 [46-48,50,60,61] years) with moderate to severe fined as a total score of ≤7 on the HAM-D-17 MDD. Eligible patients had a total score of ≥18 [46] or scale). [62,63] ≥20 on the HAM-D scale [47,48,50,60] (21-item [47,48,50,60] or not specified [46] ).

Secondary or otherwise unspecified efficacy measures included changes from baseline in the Bupropion IR dosages were fixed at 300 mg/ 30-item physician-rated Inventory of Depressive day [47] (after an initial titration period) or titrated Symptomology scale (IDS-C-30) scores, [57] HAM- within the dosage range of 225–450 [48,50,60] or D total scores, [46,48-56,59-61] MADRS total and sub- 300–450 mg/day [46,61] to achieve maximum clinical scale scores, [45] Hamilton Rating Scale for Anxiety response and tolerability (see table IV for dose- (HAM-A) scores, [46,48,50-53,55,60,61] Hospital Anxiety titration schedules). All studies had a 1-week, sin- and Depression (HAD) scores,[58] Clinical Global gle-blind, placebo lead-in period to eliminate place- Impressions of Severity of Illness (CGI-S) bo nontolerators or responders (defined as a ≥20% scores, [46-53,55,58,60,61] Clinical Global Impressions of decrease in HAM-D total scores from screening to Improvement (CGI-I) scores, [46-53,55,60,61] self-rated baseline, [46-48,50,60] or a decrease of 10 points on the 16-item Quick Inventory of Depressive HAM-D scale or a HAM-D total score of <18 at the Symptomology scores (QIDS-SR-16), [62,63] as well end of the lead-in period [61] ). © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review663 © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Table IV. Efficacy of bupropion immediate release (BUP IR) in outpatients (pts) with moderate to severe major depressive disorder. Adults aged ≥18 years received BUP IR, fluoxetine (FLU), nortriptyline (NOR), amitriptyline (AMI), doxepin (DOX), trazodone (TRA) or placebo (PL) for 6–13 wk in randomized, double-blind, single-, [61] or multi- centre [46-48,50,60] trials in >100 pts. Where reported, analyses were observed case [61] or last-observation-carried-forward [47,48,50,60] in intent-to-treat [47,48,50,60] or evaluable [61] pts; combined centre analyses are presented for one study.

[47] Values at final assessment are reported Study [duration Treatment [mean] No. of pts Mean reduction from baseline [baseline values] HAM-D CGI-I of treatment] (mg/d) a HAM-D total HAM-A CGI-S CGI-I response response score b score score score rate (% pts) crate (% pts) d Comparisons with PL Lineberry et al.

[47] BUP IR 300 e 110 12.5* [27.0] f,g 1.6* [4.4] g 1.6* [4.0] g 51* 57* [6 wk] PL 106 9.5 [27.0] f,g 1.0 [4.3] g 1.0 [3.9] g 34 40 Comparisons with other antidepressants Feighner et al. [48] BUP IR 225–450 e [345] 59 14.4 [25.3] 7.8 [15.6] 1.6 [4.2] 1.6 [4.0] 63 68 [6 wk] FLU 20–80 h [26] 60 13.1 [26.1] 7.5 [16.5] 1.5 [4.3] 1.5 [4.0] 58 58 Feighner et al.

[61] BUP IR 300–450 i 78 17.0 [25.0] g 12.5 [20.0] g 2.2 [4.4] g 2.5 [4.0] g 49 [13 wk] DOX 100–225 i 37 19.5 [26.0] g 17.0 [22.0] g 2.4 [4.6] g 2.6 [4.2] g 62 Masco et al.

[60] BUP IR 225-450 e [333] 55 10.6 [27.8] 6.7 [19.6] 1.3 [4.6] 40 58 [6 wk] NOR 75–150 j [111] 50 13.4 [28.9] 7.3 [20.5] 1.4 [4.7] 48 62 Mendels et al.

[46] BUP IR 300–450 e [372–392] 62 18.3 [26.5] 11.7 [18.9] 2.5 [4.5] 2.9 [4.2] 74 [13 wk] AMI 75–150 k [119–126] 39 17.8 [26.1] 13.2 [18.9] 2.4 [4.4] 2.5 [4.1] 79 Weisler et al.

[50] BUP IR 225–450 e [279] 59 11.0 [25.5] g 1.8 [4.7] g 56 58 [6 wk] TRA 150–400 l [168] 52 10.0 [25.0] g 1.6 [4.8] g 40 46 a Pts who had received any prior BUP, [47,48,50,60] FLU, [48] NOR [60] or TRA [50] therapy were excluded.

b Where specified, [47,48,50,60] the total score was assessed on a 21-item scale.

c Defined as ≥50% reduction from baseline in HAM-D total score.

d Defined as a CGI-I score of 1 or 2.

e Dosage titration schedules: 200 mg/d as two divided doses for 3 d, then 300 mg/d as three divided doses; [47] 225 mg/d for 3 d, then increased to 300 mg/d on day 4, which could be further increased in increments of 75 mg/d to a maximum of 450 mg/d, with at least 3 d between each dose increase; [48,50] initial dosage 225 mg/d, which could be increased in increments of 75 mg/d to a maximum of 450 mg/d, with at least 3 d between each dose increase; [60] 300 mg/d for 1 wk, increased to 450 mg/d.

[46] Dosages could be reduced to 225 mg/d in the case of intolerance.

[48,50,60] f Primary efficacy measure.

g Estimated from a graph.

h 20 mg/d could be increased in increments of 20 mg/d to a maximum of 80 mg/d, with at least 3 d between each dose increase. [48] Dosage could be reduced to 20 mg/day in the case of intolerance.

[48] i Most patients received BUP IR 300–400 mg/d and DOX 150–220 mg/d; dosage titration schedules were not stated. j 75 mg/d could be increased in increments of 25 mg/d to a maximum of 150 mg/d, with at least 3 d between each dose increase.

[60] Dosage could be reduced to 75 mg/ day in the case of intolerance.

[60] k 75 mg/d for 1 wk was increased to 150 mg/d.

[46] l 150 mg/d for 3 d, could be increased to 200 mg/d on day 4, and further increased in increments of 50 mg/d to a maximum of 400 mg/d, with at least 3 d between each dose increase. Dosage could be reduced to 150 mg/d in the case of intolerance.

[50] CGI-I = Clinical Global Impressions-Improvement of Illness scale; CGI-S = Clinical Global Impressions-Severity of Illness scale; HAM-A = Hamilton Anxiety Scale; HAM- D = Hamilton Rating Scale for Depression; * p ≤ 0.01 vs PL. 664Dhillon et al. Where reported, the proportion of patients com- Eligible patients had a total score of ≥20 on the pleting the studies in the bupropion IR and com- 17-item HAM-D, [49] ≥18 [55,56] or ≥20 [54] on the partor groups was 77% versus 76%, [47] 70% versus 21-item HAM-D, or ≥18 on the first 21 items of the 67%, [48] 64% versus 74% [60] and 58% versus 31-item HAM-D scale. [52,53] In the long-term study, 63%. [50] patients should have experienced at least one de- pressive episode within the last 60 months and must 4.1.1 Comparisons with Placebo have had ≥6 months of euthymia between the pre- Bupropion IR was effective in the treatment of vious and current episodes. [56] MDD. [47] HAM-D total, CGI-S and CGI-I scores In the short-term trials, including one in the eld- were reduced to a significantly greater extent with erly, [55] bupropion SR dosages were fixed at 150 or bupropion IR than placebo in a 6-week study (table 300 mg/day after an initial titration period [49] or IV). The proportions of responders and of patients in titrated within the dosage range of 100–300 [51,55] or remission of disease were significantly higher with 150–400 [52-54] mg/day to achieve maximum clinical bupropion IR than placebo (table IV).

response and maximum tolerability (see table V for dose-titration schedules). In the long-term trial in 4.1.2 Comparisons with Other Antidepressants 816 patients with recurrent MDD, bupropion SR Bupropion IR was as effective as the SSRI fluox- was administered at a fixed dosage of 300 mg/day etine, [48] the TCAs nortriptyline, [60] amitriptyline [46] (after an initial titration period) for 8 weeks in the and doxepin, [61] and the atypical antidepressant tra- open-label phase of the study and then patients who zodone [50] in reducing symptoms of depression and responded to therapy (patients with a CGI-I score of anxiety in 6- to 13-week trials in a total of >500 pa- 1 or 2 during the last 3 weeks) continued with this tients with moderate to severe MDD. At studyend, dosage of bupropion SR (n = 207) or placebo no significant between-group differences in the im- (n = 210) during the randomized, 44-week phase of provement from baseline in HAM-D total, HAM-A, the study. [56] CGI-S, CGI-I scores, or HAM-D or CGI-I response Where reported, the proportion of patients com- rates were observed in bupropion IR and comparator pleting the studies in the bupropion SR and placebo groups (table IV).

groups was 55% (for bupropion SR 150 mg/day), 56% (bupropion SR 300 mg/day) and 50%, [49] in the 4.2 Efficacy of Bupropion Sustained bupropion SR, sertraline and placebo groups was Release (SR) 78%, 64% and 68% [52] and 71%, 68% and 67%, [53] and in the bupropion SR, fluoxetine and placebo This section will focus on the efficacy of oral groups was 63%, 63% versus 67%. [50] bupropion SR administered twice daily as evaluated in 8- to 16-week randomized, double-blind, place- 4.2.1 Comparisons with Placebo bo- or active-controlled, multicentre trials in adults Effects on Symptoms of Depression (aged ≥18 years) [49,51-54] and elderly (aged Bupropion SR was effective in the treatment of ≥60 years) [55] patients with moderate to severe MDD in studies involving a total of >1400 adult MDD. In addition, a long-term (44-week), random- patients. [49,52-54] ized, double-blind, placebo-controlled trial evalu- ated the efficacy of bupropion SR in maintaining an Following 8 weeks of therapy, HAM-D, CGI-S antidepressive response in adults with recurrent and CGI-I total scores, where reported, were re- MDD who had previously responded to bupropion duced from baseline to a significantly (p ≤ 0.05) SR therapy during an 8-week open-label treatment greater extent with bupropion SR than with placebo period. [56] Also, a large, randomized, active-control- (table V). [49,52-54] In one study, [54] a significant be- led, multicentre trial, evaluated the efficacy of tween-group difference in HAM-D total scores in bupropion SR in patients who had no remission of bupropion SR and placebo recipients was observed symptoms or could not tolerate citalopram and were only in patients who completed the study (table V) consequently switched to [62] or augmented with [63] and not according to an LOCF analysis of data (data bupropion SR therapy. not reported); other data reported for this trial are © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review665 Table V. Efficacy of bupropion sustained release (BUP SR) in patients (pts) with moderate to severe major depressive disorder. Adult (aged ≥18 y [49,51-54] ) or elderly (aged ≥60 y [55]) pts received BUP SR, sertraline (SER), fluoxetine (FLU), paroxetine (PAR) or placebo (PL) for 8–16 wk in large (n >200), randomized, double-blind, multicentre trials. [51-54] Where specified, patients received BUP SR, SER or PAR once daily (od) or BUP SR twice daily (bid). [49,51,55] Results were last-observation-carried-forward and were estimated from graphs unless specified otherwise; values at final assessment are reported Study [duration of Treatment [mean] No. of Mean reduction from baseline [baseline values] Response treatment] (mg/d) a ptsb HAM-D total CGI-S score CGI-I score rate (% of pts) d score c Comparisons with PL Reimherr et al. [49] BUP SR 150 [147] 120 10.2* e 1.36* e 1.46* [3.9] [8 wk] BUP SR 300 f [290] 116 10.2* e 1.36* e 1.51* [4.0] PL 117 8.0 e 1.0e 1.03 [3.9] Comparisons with SSRIs Versus SER Coleman et al. [52] BUP SR 150–400 f [290] 118 21.0* [34.5] 1.9* [4.3] 66 g [8 wk] SER 50–200 h [106] 109 19.8 [34.8] 1.5 [4.3] 61 g PL 117 17.0 [34.0] 1.5 [4.3] 56 g Croft et al. [53] BUP SR 150–400 f [293] 116 18.5* [33.0] 1.2** [3.5] 66*** g [8 wk] SER 50–200 h [121] 116 19.0* [33.0] 1.2** [3.3] 68*** g PL 116 15.5 [32.5] 0.9 [3.5] 47 g Kavoussi et al. [51] BUP SR 100–300 f [238] 119 16.0 [26.0] 2.0 [4.4] 1.4 [3.4] [16 wk] SER 50–200 h [114] od 122 17.5 [25.5] 2.2 [4.4] 1.4 [3.3] Versus FLU Coleman et al. [54] BUP SR 150–400 h [319] 136 16.1* i [24.6] 56 g [8 wk] FLU 20–60 j [26] 146 15.5 i [24.5] 57 g PL 145 13.4 i [24.4] 50 g Versus PAR in elderly pts Weihs et al. [55] BUP SR 100–300 f [197] 48 17 [27.5] 1.1 [3.3] 71 [6 wk] PAR 10–40 k [22] 52 18 [27.5] 0.9 [3.3] 77 a All pts underwent a 1-wk washout/screening period prior to randomization. In some studies, patients included had no previous BUP SR, [51-53] SER, [51-53] or PAR [55] therapy.

b Number of evaluable [49,51,55] or intent-to-treat pts. [52-54] c The total score was assessed on a 17-, [49] 21- [51,54] or 31-item [52,53] scale.

d Defined as ≥50% reduction from baseline in HAM-D total score.

e Baseline values not reported.

f Dosage titration schedules: 150 mg/d od from day 1–3, then 300 mg/d (150 mg/d bid); [49] 100 mg/d from day 1–3, could be increased to 200 on day 4 and 300 mg/d on day 7; [51] 150 mg/d for at least 14 days, then could be increased to ≤400 mg/d; [52,53] 150 mg/d from day 1–7, increased to 300 mg/d on day 8, then could be increased to ≤400 mg/d on day 22 or later; [54] 100 mg/d od for 7 d, could be increased to 200 mg/d (100 mg/d bid) on day 8 or later and 300 mg/d (150 mg/d bid) on day 15 or later. [55] Dosages could be reduced to a minimum of 150 [52,53] or 300 [54] mg/d in the case of intolerance.

g Values reported (i.e. not estimated from a graph).

h Dosage titration schedules: 50 mg/d from day 1–7, could be increased to 100 mg/d on day 8, 150 mg/d on day 15 and 200 mg/d on day 22; [51] 50 mg/d from day 1–21, then could be increased to ≤200 mg/d. [52,53] Dosages could be reduced to a minimum of 50 mg/d in the case of intolerance. [52,53] i Values for patients who completed the study (BUP n = 94; FLU n = 97; PL n = 102).

j 20 mg/d from day 1–21, could be increased to 40 mg/d on day 22 or later and 60 mg/d on day 43 or later; dosage could be reduced to a minimum of 20 mg/d in the case of intolerance. [54] k 10 mg/d for 7 d, could be increased to 20, 30 and 40 mg/d on day 8, 15 and 22 or later; drug was administered od.

CGI-I = Clinical Global Impressions-Improvement of Illness scale; CGI-S = Clinical Global Impressions-Severity of Illness scale; HAM- D = Hamilton Rating Scale for Depression; SSRIs = selective serotonin reuptake inhibitors; * p ≤ 0.05, ** p < 0.01, *** p < 0.005 vs PL.

© 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 666Dhillon et al. Effects of Health-Related Quality of Life (HR-QOL) based on LOCF analyses. The reductions from base- Significant improvements from baseline in HR- line in HAM-D total, CGI-S and CGI-I scores in QOL and work place productivity were observed in patients receiving active comparators were statisti- patients receiving open-label bupropion SR during cally different from that in placebo recipients in one the initial 8 weeks of the relapse-prevention study, [53] but not in two others. [52,54] study. [56] Quality of Life in Depression Scale scores Significant (p < 0.05) improvements from base- were reduced significantly (p < 0.01) from baseline line with bupropion SR relative to placebo in HAM- (mean reduction 8.62 points) with bupropion SR, D total scores were observed at all evaluations from with a greater reduction (p < 0.001) seen in respond- day 42 onwards till study end; [53] similar improve- ers than in nonresponders to therapy (mean reduc- ments with bupropion SR relative to placebo were tion of 13.7 vs 2.4 points). [65] In terms of work place observed in CGI-S scores from day 28 onwards, [53] productivity, patients experienced a mean of 6.4 and in CGI-I scores from day 21 [53] or 28 [52] on- fewer (p < 0.001) hours of overall lost productivity wards. More (p < 0.05) patients receiving bupropion at week 8 compared with baseline. [65] SR than placebo experienced a ≥50% reduction in HAM-D total scores from day 42 onwards. [53] Relapse Prevention Bupropion SR was also effective in preventing In one study, [53] more patients responded to ther- relapse in a 52-week relapse-prevention study. [56] At apy with bupropion SR (and sertraline) than placebo study end, the median time to depression relapse (table V); however, no significant between-group (primary endpoint), based on log-rank survival differences were seen in two other studies (table curves, was significantly (p < 0.005) longer with V). [52,54] The proportion of patients with remission bupropion SR than placebo (24 vs ≥44 weeks). A (HAM-D total score <8 points by study end) was significant separation between the survival curves of significantly (p < 0.05) higher with bupropion SR bupropion SR and placebo was observed from week (but not fluoxetine) than placebo (47% vs 32%) in 12 of double-blind treatment onwards till study end.

one study. [54] In the 8-week open-label phase of a Moreover, survival estimates suggested that signifi- relapse-prevention study [56] (discussed below), ap- cantly (p < 0.005) fewer bupropion SR than placebo proximately two-thirds of patients had responded to recipients would have relapsed by study end (≈37% bupropion SR 300 mg/day therapy by the end of the vs ≈52%). [56] phase (69% according to a CGI-I score of 1 or 2; 66% based on a ≥50% reduction in HAM-D total 4.2.2 Comparisons with Selective Serotonin scores). Reuptake Inhibitors (SSRIs) Effects on Symptoms of Depression Effects on Anxiety There were no significant differences between In terms of anxiety symptoms, HAM-A scores bupropion SR and sertraline, [51-53] fluoxetine [54] or were reduced by a similar extent from baseline with paroxetine (in the elderly) [55] in terms of improve- bupropion SR, sertraline or placebo following ment in symptoms of depression in patients with 8 weeks of therapy in two studies. [52,53] However, in MDD in randomized studies of 6- to 16-weeks’ a retrospective analysis of pooled data from these duration.

studies, improvements from baseline in anxiety No significant between-group differences were symptoms were greater (p < 0.05) with bupropion observed with bupropion SR and sertraline in terms SR than placebo at day 42 and 56 according to of HAM-D total, CGI-S and CGI-I total scores HAM-A LOCF scores (LOCF mean reduction 9.9 (table V). [51-53] In one study, HAM-D total scores vs 8.4 points at week 8). [64] were reduced by ≥50% at all evaluations from day By study end, HAM-A scores reduced from base- 28 onwards with bupropion SR and day 42 onwards line by ≥50% with bupropion SR and sertraline in with sertraline therapy, [52] whereas in two other one study; [53] a similar improvement in HAM-A studies, [51,53] similar reductions in HAM-D total scores was not observed in the placebo group of this scores were observed at all evaluations from day 42 study at any evaluation. [53] onwards with both sertraline and bupropion SR ther- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review667 apy. There were no significant between-group dif- pression) trial in adult outpatients (mean age ferences in bupropion SR and sertraline recipients in≈41 years) with nonpsychotic MDD previously terms of HAM-D or CGI-I response rates. [52,53] treated with citalopram who had no remission of symptoms or could not tolerate citalopram. Remis- Similarly, no significant between-group differ- sion for patients entering the trial was defined as a ences were observed with bupropion SR and fluoxe- score of ≤5 on the clinician-rated 16-item Quick tine therapy in HAM-D total scores (observed case Inventory of Depressive Symptomology (QIDS- analysis) or in the number of responders (LOCF C-16) scale (0–27 points; higher scores indicating analysis) [table V], as well as in the proportion of greater severity of symptoms). [62,63] Patients were patients with remission (HAM-D total score <8 by either switched (n = 727) from citalopram (therapy study end; 47% vs 40%; LOCF) following 8 weeks discontinued without a taper period) to bupropion of therapy. [54] SR, sertraline or venlafaxine XR, [62] or received There was no significant difference between augmentation therapy (n = 565) [63] with bupropion bupropion SR and paroxetine therapy in terms of the SR or buspirone (see table VI for dosages and fur- mean reductions from baseline in total HAM-D ther study design details).

score (table V), CGI-I total score (table V) or CGI-S Apart from the overall duration of illness, which (values not reported) in a study in the elderly. [55] At was shorter in patients receiving bupropion SR plus 6 weeks, the number of responders (table V) and the citalopram than those receiving buspirone plus cita- proportion of patients in remission (62% vs 57%; lopram (15 vs 17 years; p < 0.05), [63] there were no CGI-I score of 1 or 2) were similar in bupropion SR significant between-group differences in patient and paroxetine recipients. [55] demographics or disease characteristics in any treat- Effects on Anxiety ment group. [62,63] In terms of anxiety symptoms, there were no Switching from Citalopram significant between-group differences in HAM-A Bupropion SR was as effective as the SSRI ser- scores with bupropion SR and sertraline therapy traline and the SNRI venlafaxine XR in patients who after 8 [52,53] or 16 [51] weeks.

were switched from citalopram therapy. [62] At In a retrospective analysis of pooled data from 14 weeks, no significant between-group differences two studies, [52,53] HAM-A scores were reduced to a were observed with regard to HAM-D-17 remission similar extent with bupropion SR or sertraline ther- rates (primary efficacy measure). There were also apy regardless of baseline anxiety levels (HAM-A no significant between-group differences in QIDS- scores ≤14, 15–19 or ≥20). [64] Responders in both SR-16 remission (defined as a total score ≤5) or treatment groups showed similar improvements QIDS-SR-16 response rates (defined as ≥50% re- from baseline in anxiety scores and the median time duction from baseline in QIDS-SR-16 total scores), to achieve clinically significant anxiolytic effect or the mean change from baseline (i.e. randomiza- (≥50% reduction from baseline in HAM-D total tion) to study end in the QIDS-SR-16 scores in scores) was 4 weeks for both groups. [64] patients receiving bupropion SR, sertraline or venla- Similarly, no significant between-group differ- faxine XR (table VI). In addition, mean times to ences in bupropion SR and paroxetine recipients remission (5.4 vs 6.2 vs 5.5 weeks) and response were reported in terms of the improvements from (5.5 vs 6.6 vs 7.0 weeks) were similar in the three baseline in HAM-A scores following 6 weeks of treatment groups. [62] therapy in the elderly (mean reduction 9.0 vs 10.5 points based on LOCF analysis; values estimat- Augmentation of Citalopram ed from a graph). [55] Bupropion SR (mean 267.5 mg/day) was as ef- fective as the serotonin receptor agonist buspirone 4.2.3 Efficacy in Patients with Prior Citalopram Therapy (mean 40.9 mg/day) when used to augment citalo- The efficacy of bupropion SR was investigated in pram therapy. [63] At study end, no significant be- the large randomized, multicentre STAR*D (The tween-group differences were observed with regard Sequenced Treatment Alternatives to Relieve De- to the HAM-D-17 remission rates (primary efficacy © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 668Dhillon et al.

Table VI. Efficacy of bupropion sustained release (BUP SR) in outpatients (pts) with major depressive disorder who had no remission (i.e did not have a score of ≤5 on clinician-rated 16-item Quick Inventory of Depressive Symptomology scale [QIDS-C-16]) of symptoms or could not tolerate citalopram (CIT). Adult (mean age ≈41 years) pts were switched from CIT to flexible-dose BUP SR, sertraline (SER) or venlafaxine extended release (VEN XR), [62] or received CIT augmented with flexible-dose BUP SR or buspirone (BUS) [63] for up to 14 weeks in the randomized, multicentre STAR*D trial. Pts receiving augmentation therapy had received prior therapy with CIT 55 mg/d (mean final dosage) for a mean of 11.9 weeks prior to randomization [63] (dosage and duration of prior CIT therapy not reported in pts switching therapy [62]). Analyses were based on logic-regression models in the intent-to-treat population; patients with missing 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores were assumed not to have had remission. [62,63] Values at final assessment are reported Study Treatment (mg/d) HAM-D-17 QIDS-SR-16 QIDS-SR-16 Mean reduction from baseline in [no. of pts] remission rate a remission rate b response rate c QIDS-SR-16 score d (% of pts) (% of pts) (% of pts) [values at baseline] In pts switched from CIT e Rush et al [62] BUP SR 150–400 f [239] 21 26 26 2.8 [13.3] SER 50–200 g [238] 18 27 27 3.2 [13.3] VEN XR 37.5–375 h [250] 25 25 28 2.9 [13.1] In pts receiving augmentation therapy Trivedi et al. [63] BUP SR 200–400 f [279] 30 39 32 3.2 [11.2]* BUS 15–60 i [286] 30 33 27 2.4 [11.5] a Primary efficacy measure; defined as by a total score of ≤7 on the 17-item HAM-D scale.

b Defined as a score of ≤5 at study end.

c Defined as a ≥50% reduction in score at randomization.

d The score at randomization was considered baseline.

e Citalopram therapy was discontinued without a taper period.

f Dosage titration schedules: 150, 200 mg/d for 7 d, then increased to 200, 300 and 400 mg/d from day 8, 28 and 42, respectively; [62] 200 mg/d for 2 wk, increasing to 300 by wk 4 and 400 mg/d during wk 6; drug was administered twice daily. [63] g 50 for 14 d, then increased to 100, 150 and 200 mg/d on day 14, 28 and 63, respectively. [62] h 37.5 for 7 d, then increased to 75, 150, 225, 300 and 375 mg/d on day 8, 15, 28, 42 and 63. [62] i 15 mg/d during wk 1, increasing to 30, 45 and 60 mg/d during wk 2, 3–5 and 6, respectively; drug was administered twice daily. [63] QIDS-SR-16 = self-rated 16-item Quick Inventory of Depressive Symptomology scale; * p < 0.05.

measure) or QIDS-SR-16 remission or response≥65 years) [44] outpatients with moderate to severe rates in patients receiving bupropion SR plus citalo- MDD. Bupropion was titrated (depending on clin- pram or buspirone plus citalopram therapy (table ical response or tolerability) to reach a target dose of VI). However, at 14 weeks, there was a significantly 300–450 [57-59] or 150–300 [44,45] mg/day (see table greater reduction from baseline in the QIDS-SR-16 VII for dose-titration schedule). At screening and score with bupropion SR plus citalopram than bus- baseline, patients had a total score of ≥17, [59] or pirone plus citalopram (table VI). The QIDS-SR-16 ≥19 [58] on the HAM-D-17 scale, or a score of ≥25 on score at study end was also significantly (p < 0.05) the IDS-IVR-30 scale. [57] One study prospectively lower with bupropion SR plus citalopram than bus- included patients exhibiting symptoms of decreased pirone plus citalopram (8.0 vs 9.1 points). The mean energy, pleasure and interest (a total score of ≥7 and time to QIDS-SR-16 remission (6.3 vs 5.4 weeks) a minimum score of 1 on ≥4 of the 5-item subset and QIDS-SR-16 response (6.3 vs 6.8 weeks) were [items 19, 20, 21, 22 and 30] of the IDS-IVR-30) [57] similar in the two treatment groups. [63] and another included patients with a CGI-S score of ≥4 (moderately ill) at both screening and base- 4.3 Efficacy of Bupropion Extended/Modified line. [59] Patients with a >25% increase or decrease in Release (XR) the IDS-IVR-30 or HAM-D-17 total scores between screening and baseline were excluded from the stud- The efficacy of bupropion XR was evaluated in ies. [57,59] Two of these studies (WXL101497 and randomized, double-blind, placebo- or active-con- AK130939) are presented only as part of an abstract trolled multicentre trials of 8–12 weeks’ duration in adult (aged ≥18 years) [45,57-59] or elderly (aged and poster presentation. [45] © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review669 © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Table VII. Efficacy of bupropion extended/modified release (BUP XR) in outpatients (pts) with moderate to severe major depressive disorder. Adult (aged ≥18 y [45,57-59] ) or elderly (aged ≥65 y [44]) pts received BUP XR once daily (od), escitalopram (ESC) od, venlafaxine extended release (VEN XR) od or placebo (PL) for 8–12 wk in randomized, double-blind, multicentre trials. Results were last-observation-carried-forward for the intent-to-treat [44,57,58] or evaluable population [45,59] unless stated otherwise; values at study end/exit are reported. Two studies (WXL101497 and AK130939) are presented only as part of an abstract and poster.

[45] Some data were obtained from the GlaxoSmithKline clinical trials registry [66,67] Study [duration Treatment (mg/d) No. of Mean reduction from baseline [baseline values] Response a Remission b CGI-I c of treatment] [mean] pts IDS-IVR-30 total MADRS total HAM-D-17 total rate (% pts) rate (% pts) response rate score score score (% pts) Comparisons with PL only Jefferson et al.

[57] BUP XR 300–450 d 133 21.3* [45.9] e,f 53 41* 53* [8 wk] PL 137 17.6 [46.0] e,f 45 27 38 In elderly pts Hewett et al. [44] BUP XR 150–300 210 13.9 [29.5] e 53* g 60* g [10 wk] PL 204 12.4 [29.8] e 43g 40g Comparisons with ESC Clayton et al.

[58] (study 1) BUP XR 300–450 d [323] 134 13.2 [23.9] e 61 40* 65 [8 wk] ESC 10–20 h [13] 133 14.2* [23.3] e 68* 49** 69 PL 130 12.1 [23.3] e 53 31 59 Clayton et al.

[58] (study 2) BUP XR 300–450 d [309] 129 13.1 [23.2] e 63 46 69* [8 wk] ESC 10–20 h [13] 133 12.9 [23.3] e 62 42 66 PL 126 11.9 [23.3] e 51 38 55 Comparisons with VEN XR Thase et al. [59] BUP XR 300–450 d [300] 160 13.7 [24.9 i]g,j 54g 37† g 68 [12 wk] [45,68] VEN XR 150–225 k [150] 164 12.8 [24.1 i]j,g 48g 28g 60 Thase et al.

[45] BUP XR 150–300 d 187 16.0* [30.4] e,f,g 57* 47* 68* (WXL101497) [8 wk] VEN XR 75–150 k 182 17.1* [30.0] e,f,g 65* 51* 65* PL 197 13.5 [30.4] e,f,g 46 32 53 Thase et al.

[45] BUP XR 150–300 d 202 14.7 [30.6] e,f,i 57 45 57 (AK130939) [8 wk] [66] VEN XR 75–150 k 193 17.0**‡ [30.1] e,f,i 66* 56* 69* PL 186 13.2 [30.6] e,f,i 49 38 50 a Defined as the proportion of pts with ≥50% reduction from baseline in IDS-IVR-30, [57] MADRS [45] or HAM-D-17 [58,59] total score.

b Defined as the proportion of pts with a final IDS-IVR-30 score ≤15, [57] HAM-D-17 total score ≤7 [58,59] or MADRS score ≤11.

[45] c Defined as the proportion of pts with a CGI-I score of ‘much’ or ‘very much’ improved/a score of 1 or 2.

[45,57-59] Continued next pag e 670Dhillon et al. Where reported, the proportion of patients com- pleting the studies in the bupropion XR and placebo groups was 76% and 79%, [57] in the bupropion XR, escitalopram and placebo groups was 77%, 76% and 72% in study 1 and 73%, 73% and 80% in study 2 [58] and in the bupropion XR and venlafaxine XR groups was 58% versus 54%. [59] 4.3.1 Comparisons with Placebo Effects on Symptoms of Depression Of the six studies (five in adults [45,57-59] and one in the elderly [44] ) in patients with MDD, bupropion XR relative to placebo demonstrated greater improve- ment from baseline in primary efficacy measures in two studies [45,57] (see table VII for study design and details). Benefit with respect to some secondary outcomes was observed with bupropion XR relative to placebo in five of the six efficacy stud- ies. [44,45,57-59] In a placebo-controlled study in patients with prominent symptoms of decreased energy, pleasure and interest, at week 8, the IDS-IVR-30 total score (primary efficacy measure) was reduced from base- line to a significantly greater extent with bupropion XR relative to placebo (table VII). [57] Significant differences (p < 0.05) between bupropion XR and placebo were also seen in response rates based on the IDS-IVR-30 total scores at weeks 1 and 2. [57] In addition, IDS-C-30-derived (50% vs 35%) and CGI- I-derived (table VII) response rates were significant- ly (p < 0.05) higher in recipients of bupropion XR at week 8 or study exit. [57] Clinician- (table VII) or patient-rated (IDS-C-30 score ≤13; 32% vs 18%) remission rates were also significantly (p < 0.05) greater with bupropion XR than placebo. [57] Furthermore, in this study, [57] symptoms of ener- gy, pleasure, interest and insomnia improved signif- icantly from baseline with bupropion XR relative to placebo by week 8 or study exit. IDS-IVR-30 and IDS-C-30 subset scores assessing these symp- toms showed significantly greater improvements (p < 0.05) from baseline (figure 1), with significant improvements in symptoms of energy, pleasure and interest observed from week 1 onwards. No signif- icant between-group differences were seen in bupro- pion XR and placebo recipients with respect to anxiety symptoms (figure 1). © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Table VII. Contd d Dosage titration schedules: 150 mg/d for 1 wk, 300 mg/d for 3 wk, then then could be increased to 450 mg/d; [57,58] 150 mg/d for 3 wk, then 150–300 mg/d; [44] 150 mg/d for 1 wk, 300 mg/d for 4 wk, then 300–450 mg/d (dosage to be increased if HAM-D-17 score did not improve by >50% from baseline) for 7 wk, followed by a taper period of ≤2 wk at study end when dosage decreased to 300 mg/d for 1 wk then 150 mg/d for 1 wk before being stopped; [59] 150 mg/d for 4 wk, then 150–300 mg/d.

[45] Dosages could be reduced to a minimum of 300 mg/d in case of intolerance.

[57-59] e Primary efficacy measure.

f Least-squares mean.

g Estimated from a graph.

h 10 mg/d for 4 wk, then could be increased to 20 mg/d; dosage could be reduced to 10 mg/d in case of intolerance. [58] i Data obtained from the GlaxoSmithKline clinical trials registry.

[66,67] j Mixed-model repeated measure analysis.

k Dosage titration schedules: 75 mg/d for 1 wk, 150 mg/d for 4 wk, then 150–225 mg/d for 7 wk (dosage to be increased if HAM-D-17 score did not improve by >50% from baseline; dosage could be reduced to 150 mg/d in case of intolerance), followed by a taper period of ≤2 wk at study end when dosage was decreased to 150 mg/d for 1 wk then 75 mg/d for 1 wk before being stopped; [59] 75 mg/d for 4 wk, then 75–150 mg/d for 4 wk, followed by a taper period of ≤1 wk at study end when dosage decreased to 75 mg/d prior to being stopped.

[45] CGI-I = Clinical Global Impressions-Improvement of Illness scale; HAM-D-17 = 17-item Hamilton Rating Scale for Depression; IDS-IVR-30 = self-rated version of the Inventory of Depressive Symptomology 30-item scale; MADRS = Montgomery- Asberg Depression Rating Scale; * p < 0.05, ** p < 0.005 vs PL; † p < 0.05 vs VEN XR; ‡ mean treatment difference between BUP XR and VEN XR 2.3 (95% CI 0.3, 4.3). Bupropion: A Review671 0 −1 −2 −3 −4 −5 −6 −7 −8Energy, pleasure and interestInsomnia * * ** *AnxietyEnergy, pleasure and interest Insomnia IDS-IVR-30 scale IDS-C-30 scale Anxiety Mean change from baseline BUP PL Fig. 1. Efficacy of bupropion extended/modified release (BUP XR) in patients with major depressive syndrome exhibiting symptoms of decreased energy, pleasure and interest. Least squares mean change from baseline in the energy, pleasure and interest subset and the insomnia and anxiety subset scores are presented in the figure. [57] Patients received BUP XR 300–450 mg/d (n = 133) or placebo (PL) [n = 137] for 8 weeks in a randomized, double-blind, placebo controlled trial. [57] IDS-IVR-30 = 30-item self-rated Inventory of Depressive S ymptomolo gy; IDS-C-30 = 30-item physician-rated Inventor y of De pressive S ymptomolo gy; * p < 0.05, ** p < 0.001 vs PL. Of the two placebo-controlled studies in which not study 1 (1.9 vs 1.6 points)], and in the pooled venlafaxine XR was the active comparator, [45] one analysis (1.9 vs 1.6 points) of data from both studies.

study (WXL101497) showed greater improvement Significant (p < 0.05) reductions from baseline in from baseline in MADRS total score (primary effi- HAD scores in bupropion XR relative to placebo cacy measure) in bupropion XR relative to placebo were also observed in the individual studies (11.0 vs recipients, whereas the other study (AK130939) did 8.6 points in study 1 and 9.9 vs 7.5 points in study 2) not show significant differences between the two and in the pooled analysis (10.5 vs 8.1 points).

groups (table VII). However, MADRS total score Escitalopram showed generally similar results in was reduced from baseline to a significantly greater terms of the CGI-I and HAD scores. [58] extent with venlafaxine XR therapy relative to pla- Response rates based on HAM-D-17 total scores cebo in both studies (table VII). [45] were similar in bupropion XR and placebo recipi- MADRS and CGI-I response rates and remission ents in individual studies (table VII), but higher with rates were significantly higher with bupropion XR bupropion XR than placebo in the pooled analysis than placebo in study WXL101497 but not in (62% vs 52%; p < 0.05). [58] HAM-D-17 response AK130939 (table VII). [45] However, these para- rates were higher with the active comparator, escita- meters were significantly higher with venlafaxine lopram, relative to placebo in study 1 (but not study XR than placebo in both studies (table VII). [45] 2) [table VII] and the in the pooled analysis (65% vs In the two placebo-controlled trials in which esci- 52%; p = 0.001). CGI-I response rates were higher talopram was the active comparator, [58] there were with bupropion XR than placebo in study 2 (but not no statistical differences between bupropion XR and study 1) [table VII] and in the pooled analysis of placebo recipients in terms of primary efficacy mea- both studies (67% vs 57%; p < 0.05). No significant sure (HAM-D-17 total score; table VII); a retrospec- between-group differences were seen in escitalo- tive pooled analysis [58] of the two studies also did pram and placebo recipients in studies 1 and 2 in not show significant between-group differences in terms of CGI-I response rates, but in the pooled the HAM-D-17 total scores. However, benefit with analysis of these studies, response rates were higher bupropion XR relative to placebo was observed with with escitalopram than placebo (67% vs 57%; respect to some secondary efficacy measures. CGI-S p < 0.05). Remission rates were higher with both scores reduced from baseline to a significantly bupropion XR and escitalopram relative to placebo (p < 0.05) greater extent in bupropion XR than in study 1 (table VII) and in the pooled analysis placebo recipients in study 2 (2.0 vs 1.6 points) [but (43% for bupropion XR and 45% for escitalopram © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 672Dhillon et al.

vs 34% for placebo; both p < 0.05), but not in study apy in terms of the improvement from baseline in 2 (for either treatment group relative to placebo) HAM-D-17 total score (primary efficacy measure), [table VII]. [58] HAM-D-response, CGI-I response rates, and remis- sion rates in adults with MDD in two 8-week, place- In a 10-week study in elderly patients with MDD, bo-controlled studies (also see discussion in section no significant between-group differences with 4.3.1 and table VII for study design and details).

bupropion XR and placebo were observed in terms These findings were confirmed in a retrospective of the change from baseline in MADRS total score pooled analysis of data from the two studies. [58] at 10 weeks (LOCF ANCOVA mean treatment dif- ference 1.5 [95% CI – 3.2, 0.2]), the protocol speci- 4.3.3 Comparisons with Venlafaxine fied primary efficacy measure. [44] However, rank Extended Release analysis of covariance (mean treatment difference Effects on Symptoms of Depression 4.0) and robust regression analysis (mean treatment The efficacy of bupropion XR was compared difference 1.9) demonstrated significant (p < 0.05) with the SNRI venlafaxine XR in >1200 adults with differences between bupropion XR and placebo re- MDD in three randomized studies (see table VII for cipients in the reduction from baseline in MADRS study design and details). [45,59] Following 8 [45] or total scores; [44] these analyses were considered ap- 12 [59] weeks of therapy, there were no significant propriate by independent experts to account for out- between-group differences in terms of the change liers largely in the placebo group who experienced a from baseline in MADRS (primary efficacy mea- large improvement (15–30 points) in MADRS total sure; mean treatment difference 1.1 [95% CI – 0.7, scores prior to withdrawal from study. [31] In addi- 2.9]) [45,67] or HAM-D-17 (secondary efficacy mea- tion, there were significant (p < 0.05) reductions sure) [59] total scores in two studies (table VII). How- from baseline in the MADRS total scores according ever, in the third study (AK130939), venlafaxine to observed case (mean treatment difference 3.0 XR was significantly better than bupropion XR in [95% CI – 4.7, – 1.4]) or per protocol ANCOVA terms of MADRS scores (mean treatment difference (mean treatment difference 2.8 [95% CI – 4.7, – 0.9]) 2.3 [95% CI 0.3, 4.3]). [59,66] analyses in bupropion XR versus placebo recipients In one study [59] a >50% reduction in the HAM- (protocol-defined secondary efficacy measures).

D-17 total score was observed in both bupropion XR Similarly, MADRS and CGI-response rates were and venlafaxine XR treatment groups by study significantly higher with bupropion XR than place- end. [59] Additionally, both therapies resulted in simi- bo at week 10 (table VII). [44] lar improvements on the sub-scales of depressed Effects on HR-QOL mood, Bech Melancholia Scale and the anxiety sub- In elderly patients with MDD, [44] most functional scale of the HAM-D-17 scale. Response rates and HR-QOL outcomes improved significantly (HAM-D-17 scale or CGI-I scale; LOCF; see table from baseline in bupropion XR relative to placebo VII) were also similar in both treatment groups.

recipients following 10 weeks of therapy. At week However, remission rates were significantly higher 10, greater improvements (p ≤ 0.05) from baseline in recipients of bupropion XR than venlafaxine XR were observed in functional outcomes assessed by (LOCF; see table VII). [59] Sheehan Disability Scale scores (mean – 7.8 vs – 5.7) and in HR-QOL assessed by Short Form Quality of 4.4 Meta-Analyses Life Enjoyment and Satisfaction Questionnaire life Two meta-analyses compared efficacies of satisfaction and contentment (1.2 vs 0.9), and the bupropion SR and IR versus SSRI or placebo recipi- Motivation and Energy Inventory (23.6 vs 16.9) ents, [69] or of bupropion SR and XR versus SSRI or scores with bupropion XR relative to placebo (val- placebo recipients [19] in patients with moderate to ues are means based on LOCF analyses). [44] severe MDD. 4.3.2 Comparisons with Escitalopram In the meta-analysis (ITT LOCF analysis) com- No significant differences were observed be- paring bupropion IR and SR (n = 732) with SSRIs tween bupropion XR and escitalopram (SSRI) ther- (n = 731) or placebo (n = 512), [69] data relating to © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review673 response and remission rates from seven 6- to placebo. [19] Moreover, fewer (p < 0.005) bupropion 16-week randomized trials were pooled together, of than SSRI recipients with remission of disease ex- which six [48,51-55] trials in adult [48,51-54] or elderly [55] perienced residual fatigue (19.5% vs 30.2%). [19] patients have been discussed in detail in sections 4.1 5. Tolerability and 4.2. Also included in the analysis was a pre- viously unpublished trial [69] in patients receiving This section will focus on data obtained from bupropion SR (n = 138), fluoxetine (n = 133) or pooled analyses of trials in patients with MDD in- placebo (n = 134). In these trials, patients received volving bupropion IR, [7,69] SR [8,69] or XR. [70] Two of bupropion IR 225–450 mg/day, [48] bupropion SR these pooled analyses were presented in the manu- 100–400 mg/day, [51-55] sertraline 50–200 mg/ facturer’s prescribing information, [7,8] one analysis day, [51-53] fluoxetine 20–80 mg/day, [48,54] paroxetine was discussed in section 4.4 and another was pre- 10–40 mg/day [55] or placebo. [52-54] sented as an abstract and poster (see figure 2 for In the other meta-analysis (ITT LOCF analysis) details). [70] comparing bupropion SR and XR (n = 662) with SSRIs (n = 655) or placebo (n = 489), [19] data were 5.1 General Profile pooled from six 6- to 16-week randomized studies in adults [51-53,58] or elderly [55] (see 4.2 and 4.3). [58] In All three formulations of bupropion were gener- these trials, patients received bupropion SR ally well tolerated in adult (aged ≥18 years) or 100–400 mg/day, bupropion XR 300–450 mg/day, elderly (aged ≥65 years) patients with MDD, with sertraline 50–200 mg/day, [51-53] paroxetine the tolerability profiles of bupropion IR, SR and XR 10–40 mg/day, [55] escitalopram 10–20 mg/day [58] or being generally similar. [7,8,70] placebo. [52,53,58] Overall, the most common treatment-emergent According to data from one meta-analysis, more adverse events reported with bupropion (IR, SR or patients receiving bupropion (IR or SR) or SSRIs XR) or placebo were headache (20–26% vs (sertraline, fluoxetine or paroxetine) than placebo 20–23%), dry mouth (16–28% vs 7–18%) and nau- responded to therapy or were in disease remission sea (13–23% vs 8–19%); agitation was another com- after 6–16 weeks of therapy. [69] Response (62% and mon treatment-emergent adverse event reported in 63% vs 51%) and remission (47% and 47% vs 36%) 32% of bupropion IR compared with 22% of place- rates were similar in bupropion and SSRI recipients bo recipients. [7,8,70] and higher (p < 0.01) than those in placebo recipi- Individually for each formulation:

ents.

In a pooled analysis, following 3–4 weeks of therapy, commonly reported treatment-emergent ad- According to data from the other meta-analysis, verse events occurring in ≥3% of bupropion IR patients receiving bupropion (SR or XR) experi- 300–600 mg/day (n = 323) recipients and with a enced more resolution of sleepiness and fatigue than frequency twice that of placebo (n = 185) were those receiving SSRIs (sertraline, paroxetine or esci- tremor (22% vs 8%), menstrual complaints (5% vs talopram) after 6–16 weeks of therapy. [19] Bupro- 1%), hypertension (4% vs 2%), impaired sleep qual- pion (SR or XR) recipients experienced a greater ity (4% vs 2%), anxiety (3% vs 1%) and gustatory (p < 0.001) reduction from baseline in hypersomnia disturbance (3% vs 1%). [7] scores (HAM-D scale items 22, 23 and 24 scores) than SSRI or placebo recipients (1.1 vs 0.9 and The most frequent treatment-emergent adverse 0.9 points). Furthermore, fewer (p < 0.005) bupro- events occurring in ≥5% of bupropion SR 300 or pion than SSRI recipients with remission of disease 400 mg/day recipients and with a frequency twice experienced residual hypersomnia (20.5% vs that of placebo in a pooled analysis of placebo- 32.1%). [19] Fatigue scores (HAM-D scale item 13 controlled trials in patients with MDD are summa- scores) also reduced from baseline to a significantly rized in figure 2, with dry mouth, nausea, insomnia greater (p < 0.01) extent with bupropion than SSRIs and dizziness being the most commonly reported or placebo (1.1 vs 0.9 and 0.8); SSRI therapy also according to these criteria. [8] These results are sup- significantly (p < 0.0005) reduced fatigue relative to ported by data from another pooled analysis [71] of © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 674Dhillon et al. BUP XR 150−450 mg/d ESC 10−20 mg/d VEN XR 75−150 mg/d PL 0 5 10 15 20 25 Dry mouth Nausea Somnolence Insomnia Excess sweatingFatigue Decreased apetiteIncidence (% of patients) bBUP SR 300 mg/d BUP SR 400 mg/d PL Dry mouth Nausea Insomnia Dizziness Pharyngitis Agitation Abdominal pain Myalgia Palpitation Tinnitus Sweating Tremor Anxiety Rash Anorexia Urinary frequency 0 5 10 15 20 25 30aIncidence (% of patients) Fig. 2. Tolerability profile of bupropion sustained release (BUP SR) and bupropion extended/modified release (BUP XR) in patients with major depressive disorder (MDD). Pooled incidences of treatment-emergent adverse events (a) occurring in ≥5% of bupropion SR recipients and with a frequency twice that of placebo (PL) in patients receiving BUP SR 300 or 400 mg/d (n = 376 or 114) or PL (n = 385) in clinical trials (duration of treatment not reported; clinical trials and the age of patients not identified); [8] and (b) occurring in >5% of patients in any treatment group and with a frequency twice that of PL in patients receiving BUP XR 150–450 mg/d (n = 801), escitalopram (ESC) 10–20 mg / d (n = 281), venlafaxine extended release (VEN XR) 75–150 mg/d (n = 385) or PL (n = 796) for 8 weeks in four active- [45,58] and one placebo- controlled [57] trial in adults with moderate to severe MDD. [70] three 8-week trials (one of which is fully pub- leading to withdrawal from therapy included lished [49] ) in which the incidences of dry mouth neuropsychiatric disturbances (mainly agitation and (16% vs 7%), nausea (13% vs 8%) and insomnia mental disturbances) in 3% of patients, gastrointesti- (11% vs 7%) were significantly (p < 0.05) higher nal disturbances (mainly nausea and vomiting) in with bupropion SR 100–400 mg/day (n = 987) than 2% of patients and neurological disturbances (main- placebo (n = 385).

ly seizures, headaches and sleep disturbances) in 2% The most frequent treatment-emergent adverse of patients. [7] events occurring in >5% of bupropion XR recipients Similarly, in pooled data from bupropion SR and with a frequency twice that of placebo in a trials, [8] adverse event-related withdrawal rates were pooled analysis were dry mouth, insomnia and ex- 9% in bupropion SR 300 mg/day, 11% in bupropion cess sweating (figure 2). [70] SR 400 mg/day and 4% in placebo recipients. The Most (89–99%) adverse events associated with most frequent (incidence ≥1%) adverse events lead- bupropion SR 100–400 mg/day, [71] bupropion XR ing to withdrawal of therapy were rash (2.4% and 300–450 mg/day [57] or placebo were mild to moder- 0.9% in bupropion SR 300 and 400 mg/day vs 0% in ate in severity. [49,57,71] placebo recipients), nausea (0.8% and 1.8% vs The adverse event-related withdrawal rate in 0.3%), agitation (0.3% and 1.8% vs 0.3%) and mi- 2400 bupropion IR recipients (patients with MDD or graine (0% and 1.8% vs 0.3%). [8] More (p < 0.05) volunteers participating in clinical trials undertaken during drug development) was ≈10%. [7] Symptoms bupropion SR than placebo recipients withdrew be- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review675 cause of adverse events (7% vs 4%) in another The incidence of discontinuation symptoms due pooled analysis. [71] to cessation of therapy during a 2-week taper period when bupropion XR dosage was reduced from 300 Adverse event-related withdrawal rates in bupro- to 150 mg day was 14% compared with 18% in pion XR and placebo recipients were 5% and 4% in patients who continued with placebo, and in the a pooled analysis in adult patients. [70] In one 2 weeks following discontinuation of therapy, the study, [57] adverse events leading to withdrawal of incidence was 9% with bupropion XR and 12% with therapy in at least two bupropion XR recipients were placebo. [9] headache (two patients) and rash (two patients). [57] In another study, dizziness (1%) and anxiety (1%) 5.2 Serious Adverse Events were the most common causes of withdrawal from therapy. [59] Serious adverse events related or potentially re- In the long-term study, [56] headache (16% vs lated to therapy occurred in <1% of bupropion IR, 13%), infection (10% vs 5%) and rhinitis (7% vs SR or XR recipients in individual studies [50,53,54] or 4%) were the most frequent treatment-emergent ad- pooled analyses [69,70] following 6–16 weeks of ther- verse events reported in bupropion SR and placebo apy. One patient receiving bupropion IR 300 mg/ recipients after 52 weeks of therapy; the incidence day was hospitalized because of grand mal of other adverse events, including nausea, insomnia seizure. [50] In bupropion SR 150–400 mg/day recipi- and dry mouth, was ≤5% in bupropion SR and ents, serious adverse events related to or potentially placebo recipients. [56] related to therapy included allergic reaction (one No overall differences in the tolerability of patient) [53] and serum sickness-like reaction (one bupropion IR or SR in elderly versus adult patients patient).[54] Two potentially drug-related serious ad- with MDD were observed. [8] Similarly, in elderly verse events (siezure and anaphylaxis) were report- patients receiving bupropion XR, the nature and ed during an initial 8-week open-label phase of a incidence of treatment-emergent adverse events long-term (52-week) trial; no drug-related serious were generally similar to those in adults, with the adverse events were reported during the 44-week most frequent treatment-emergent adverse events double-blind period of this trial. [56] There were no occurring in ≥3% of bupropion XR 150–300 mg/day reports of seizures, suicide, suicidal ideation or in- recipients and with a frequency 1.5 times that of tentional self-harm in bupropion XR recipients in a placebo being dry mouth (9% vs 5%), constipation pooled analysis of 8-week trials. [70] (6% vs 3%) and insomnia (6% vs 4%). [44] 5.2.1 Seizures Bupropion SR (shortly after commencing ther- There is a dose-dependent risk of seizures asso- apy) has been associated with symptoms of in- ciated with the use of bupropion IR, [7] SR [8] and creased restlessness, agitation, anxiety and insomnia XR, [9] which is also dependent on patient factors in patients with MDD, which may require treatment (e.g. prior history of head trauma or seizures), clin- with sedative or hypnotic drugs. [8,9] In a pooled ical situations (e.g. excessive use of alcohol or seda- analysis of patients receiving bupropion SR 300 or tives, and addiction of opiates, cocaine or stimu- 400 mg/day or placebo, the incidences of agitation lants) and concomitant medications (e.g. antipsy- were 3%, 9% and 2%, of anxiety were 5% and 6% chotics or antidepressants).

and 3%, and of insomnia were 11%, 16% and 6%, respectively. [8] Symptoms in 1% and 2.6% of bupro- Bupropion IR 300–450 mg/day was associated pion SR 300 and 400 mg/day and in 0.8% of placebo with a seizure incidence of ≈0.4% (13 of >3200 pa- recipients were severe enough to lead to discontinu- tients assessed prospectively); [72] eight cases were ation of therapy. [8] Several neuropsychiatric symp- reported during 8 weeks’ therapy and five in patients toms, including delusions, hallucinations, psychosis continuing therapy for an unlimited duration. In and paranoia, have been associated with bupropion addition, the estimated seizure incidence increased IR or SR therapy, which in some cases abated upon≈10-fold with higher doses of bupropion IR dose reduction or withdrawal of therapy. [8] (450–600 mg/day). [7] © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 676Dhillon et al. Bupropion SR 100–300 mg/day is associated than TCA recipients. Bupropion IR, compared with with a seizure incidence of 0.1% (3 of 3100 patients the TCAs nortriptyline or doxepin, was associated assessed prospectively), which increases to 0.4% with significantly (p < 0.05) less somnolence (3% vs with bupropion SR 400 mg/day. [8] 14%, [60] 12% vs 39% [61] ), tachycardia (2% vs 12% [60] ), dry mouth (35% vs 61%, [60] 33% vs Bupropion XR ≤450 mg/day is associated with a 56% [61] ), constipation (27% vs 43%), [61] tiredness seizure incidence of 0.1% in clinical trials. [10] There (12% vs 33% [61] ) or increased appetite (3% vs were no reports of seizures in 801 bupropion XR 34% [61] ). Adverse event-related withdrawal rates in recipients in pooled data from five clinical trials. [70] patients receiving bupropion IR or TCAs (nortripty- Since a higher dose of bupropion (IR, SR or XR) line, amitriptyline or doxepin) were 8–17% and increases the risk of seizures, caution is advised 7–21%. [46,60,61] during dose incrementation and patients should not exceed the maximum recommended dosage (see 5.3.2 Versus an Atypical Antidepressant section 6). [7-10] The nature of adverse events associated with 5.2.2 Suicide bupropion IR was generally similar to that with the Suicide is a known risk associated with MDD atypical antidepressant trazodone in a clinical trial in irrespective of whether or not patients are receiving patients with MDD (see section 4.1 for study de- antidepressant therapy. [9] However, pooled analyses signs and details). [50] The most common (incidence of short-term antidepressant trials (SSRIs and >20% in any group) adverse events in the two others) [24 short-term trials of 9 antidepressants in groups were headache (34% vs 23%), dry mouth >4400 children and adolescents and 295 short-term (31% vs 27%), dizziness (21% vs 30%) [50] and som- (median duration 2 months) trials of 11 antidepres- nolence (8% vs 45%). [50] However, significantly sants in >77 000 adults] indicated that the risk of fewer (p < 0.05) bupropion IR than trazodone recipi- suicidality may be increased with these drugs over ents reported somnolence (8% vs 45%), appetite that observed with placebo in children and adoles- increase (0% vs 13%) and oedema (0% vs 10%), cents (14 additional cases/1000 patients treated), as whereas more (p < 0.01) bupropion IR than trazo- well as in young adults (18–24 years) [5 additional done recipients reported anorexia (13% vs 0%) and cases/1000 patients] with MDD and other psychiat- anxiety (15% vs 2%).

[50] Adverse event-related ric disorders. [9] In contrast, in these analyses, pa- withdrawal rates in the two groups were 19% and tients aged ≥24 years did not show increased risk of 25%. [50] suicidality with antidepressant therapy relative to 5.3.3 Versus SSRIs and a Serotonin-Norepinephrine placebo (one fewer case/ 1000 patients treated), Reuptake Inhibitor (SNRI) whereas the risk was reduced in patients aged The tolerability profiles of bupropion IR, SR and ≥65 years (six fewer cases/1000 patients treated). [9] XR were generally similar to those of the SSRIs It is recommended that patients receiving any fluoxetine, [48,54] sertraline, [51-53] paroxetine, [55] esci- antidepressant, including bupropion IR, SR or XR, talopram, [70] and the SNRI venlafaxine XR, [70] ac- should be monitored closely for clinical worsening, cording to data from individual clinical trials [48,51-55] suicidality or unusual changes in behaviour (see and pooled analyses [69,70,73] in patients with MDD.

section 6). [9] Adverse event-related withdrawal rates were 10% in bupropion IR, [48] 3–9% in bupropion 5.3 Comparisons with Other Antidepressants SR, [51-55] 3–13% in sertraline, [51-53] 4–6% in fluoxe- 5.3.1 Versus Tricyclic Antidepressants tine [48,54] and 6% in paroxetine [55] recipients. In one Although the nature of adverse events associated trial, [51] fewer bupropion SR than sertraline recipi- with bupropion IR was generally similar to that with ents withdrew from therapy because of adverse the TCAs nortriptyline [60] and doxepin [61] in clinical events (3% vs 13%; p < 0.005). In a meta-analysis trials in patients with moderate to severe MDD (see (see section 4.4), the most common (incidence section 4.1 for study designs and details), some >15%) adverse events in bupropion (IR or SR), adverse events were reported in fewer bupropion IR SSRI (sertraline, fluoxetine or paroxetine) or place- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review677 5.3.4 In Patients with Prior Citalopram Therapy bo recipients were headache (31%, 29% and 27%), In the large STAR*D trial in patients with MDD dry mouth (21%, 16% and 15%), nausea (17%, 21% (see section 4.2.3 for study design details), there and 14%) and insomnia (17%, 16% and 7%); serious were no significant differences in the maximal fre- adverse events occurred in <1% of patients in either quency, intensity and burden of adverse events be- group. [69] tween bupropion SR, sertraline and venlafaxine XR However, some gastrointestinal adverse events recipients in patients switching from prior citalo- (e.g. diarrhoea) and somnolence occurred less fre- pram therapy and between bupropion SR and bus- quently in bupropion (IR or SR) than SSRI recipi- pirone when both were used to augment citalopram ents according to data from two meta-analyses. [69,73] therapy. [62,63] However, discontinuation rates due to In one meta-analysis (see section 4.4), [69] after intolerance (which included all discontinuations pri- 6–16 weeks of therapy, it was observed that signifi- or to week 4, regardless of reason, and all discon- cantly fewer (p < 0.001) bupropion (IR or SR) than tinuations due to adverse events after week 4 of SSRI (sertraline, fluoxetine and paroxetine) recipi- therapy) were lower with bupropion plus citalopram ents experienced diarrhoea (8% vs 18%) and somno- than with buspirone plus citalopram therapy (12.5% lence (3% vs 12%), whereas significantly more vs 20%; p <0.001); [63] discontinuation rates due to intolerance were generally similar in patients (p < 0.05) bupropion than SSRI recipients experi- switching from citalopram to bupropion SR, ser- enced dry mouth (21% vs 16%). Similarly, in an- traline or venlafaxine XR therapy (27%, 21% and other meta-analysis of six [48,51-53,55,74] 6- to 16-week 21%). [62] randomized trials in adults or elderly patients with The incidence of serious adverse events was sim- MDD (see sections 4.1 and 4.2, and table V for ilar in patients switched from citalopram therapy to individual study design details), bupropion (IR or bupropion SR, sertraline or venlafaxine XR therapy SR) therapy was associated with a smaller risk of (2.1%, 4.2% and 2.4%); four patients were hospital- nausea (relative risk [RR] 0.6 [95% CI 0.41, 0.89]), ized for suicidal ideation or attempted suicide, none diarrhoea (RR 0.31 [95% CI 0.16, 0.57]) and som- of whom committed suicide during the study. [62] nolence (RR 0.27 [95% CI 0.15, 0.48]) than SSRI Similarly, the incidence of serious adverse events (fluoxetine, sertraline or paroxetine) therapy. [73] was similar in bupropion SR plus citalopram recipi- The tolerability profile of bupropion XR ents and buspirone plus citalopram recipients (3.6% 150–450 mg/day was generally similar to that of the vs 4.2%); no patient committed suicide during the SSRI escitalopram 10–20 mg/day and the SNRI study. [63] venlafaxine XR 75–150 mg/day in a pooled analysis 5.4 Sexual Functioning of randomized trials in adults. [70] Adverse event- related withdrawal rates were 5%, 4%, 6% and 4% The effects of bupropion SR [52-54,74] and in bupropion XR, escitalopram, venlafaxine XR and XR [45,58,59] versus those of comparators (ser- placebo recipients. Somnolence, fatigue and de- traline, [52,53] fluoxetine, [54] escitalopram, [58] venla- creased appetite were reported in at least twice as faxine XR [45,59] ) or placebo [45,52-54,58] on sexual func- many escitalopram as bupropion XR recipients (fig- tioning have been investigated in large (n >250), ure 2); similarly, somnolence, fatigue and excessive randomized, double-blind trials in patients with sweating occurred in at least twice as many venla- moderate to severe MDD (see section 4 for study faxine XR as bupropion XR recipients (figure 2).

design and details; results pertaining to sexual func- Other commonly (incidence >3%) reported adverse tioning in one study [51] were reported by Segraves et events in bupropion XR, escitalopram, venlafaxine al. [74] ). The effects of bupropion SR, SSRIs (ser- XR and placebo recipients included headache (20%, traline or fluoxetine) or placebo on sexual function- 23%, 16% and 20%), dizziness (7%, 4%, 9% and ing were also compared in two meta-analyses that 4%) constipation (7%, 3%, 4% and 4%) and diar- were discussed previously (sections 4.4 [69] and rhoea (5%, 12%, 3% and 6%) [values estimated 5.3.3 [73] ) [two trials, [48,55] which were included in the from a graph]. [70] efficacy analyses, were excluded from these analy- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 678Dhillon et al.

Table VIII. Effects of bupropion sustained release (BUP SR) on sexual functioning in patients (pts) with moderate to severe major depressive disorder. Adults aged ≥18 y received increasing dosages, if clinically indicated, of BUP SR, sertraline (SER), fluoxetine (FLU) or placebo (PL) for 8–16 wk in large (n >200), randomized, double-blind, multicentre trials (see table V for dosage details). [52-54,74] Results were last-observation-carried-forward in the evaluable [74] or intent-to-treat patients; [52-54] values at final assessment are reported Study [duration Treatment (mg/d) Sexual desire Sexual arousal Orgasm dysfunct. Pt satis. [dissatis.] of treatment] [no. of pts] disr. a (% of pts) disr. (% of pts) (% of pts) (% of pts) b Comparisons with SER Coleman et al. [52] BUP SR 150–400 [118] 17 †c 610 ††† 85† [8 wk] SER 50–200 [109] 31 c 9 36** 62* PL [117] 20 c 10 14 81 Croft et al. [53] BUP SR 150–400 [116] 19* † 6*†c 16†††c 75†c [8 wk] SER 50–200 [116] 28 12* c 40** c 64* c PL [116] 31 2 c 9c 77c Segraves et al. [74] BUP SR 10–300 [119] 21 † 4†† 8††† 79††† [16 wk] SER 50–200 [122] 34 16 52 58 Comparisons with FLU Coleman et al. [54] BUP SR 150–400 [136] 14 †c 7c 11†††c [3†c] [8 wk] FLU 20–60 PL [46] 24* c 12c 30** c [23* c] PL [145] 13 c 9c 10c [7c] a At baseline the proportion of patients with sexual desire disr. were 46–54%, [74] 27–33%, [52] 39–46% [53] and 14–24%. [54] b Apart from one study, [54] all studies reported the proportion of pts satisfied at study end; one study reported the proportion of pts who were dissatisfied among those who had been satisfied at baseline. [54] c Estimated from a graph.

disr. = disorder; dissatis. = dissatisfaction; dysfunct. = dysfunction; Pt = patient; satis. = satisfaction; * p < 0.05, ** p < 0.001 vs PL; † p < 0.05, †† p ≤ 0.005, ††† p < 0.001 vs active comparator. 5.4.1 Comparisons with Placebo ses as they did not assess effects on sexual function- In terms of sexual functioning, bupropion SR and ing; patients with sexual desire disorders at baseline XR were generally well tolerated in patients with were also excluded [69] ].[69,73] moderate to severe MDD. [45,52-54,58] In the bupropion SR studies, [51-54,74] sexual func- tioning was evaluated in investigator-conducted Bupropion SR structured interviews assessing several parameters, The proportion of patients with sexual desire including the proportion of patients with sexual de- disorder, sexual arousal disorder or orgasm dysfunc- sire disorder, sexual arousal disorder or orgasm dys- tion, and the proportion of patients expressing satis- function, and the proportion of patients satisfied/ faction with overall sexual functioning were gener- dissatisfied with their overall sexual functioning. In ally similar in bupropion SR and placebo recipients the bupropion XR studies, sexual functioning was after 8 weeks’ therapy (table VIII). [52-54] In one evaluated by a validated measure, the Changes in study, [53] significantly fewer bupropion SR than pla- Sexual Functioning Questionnaire (CSFQ) total cebo recipients experienced sexual desire disorder; scores [45,58,59] (primary outcome measure in one however, more bupropion SR than placebo recipi- study) [59] and CSFQ subscale (pleasure, desire/fre- ents experienced sexual arousal disorder (table quency, desire/interest, arousal and orgasm) scores.

VIII). [53] Sexual dysfunction (defined as the proportion of In contrast, sertraline and fluoxetine therapy rela- patients with orgasm dysfunction at week 8) was tive to placebo were associated with worsening of assessed by investigator interviews in one study sexual function as indicated by a significantly great- (primary measure although it is a nonvalidated in- er proportion of patients experiencing orgasm dys- strument). [58] It should be noted that patients with function [52-54] or sexual desire disorder, [54] and with sexual desire disorder at baseline were permitted to fewer patients expressing overall sexual satisfac- participate in some studies. [52-54,58,74] tion [52,53] or more patients expressing dissatisfaction © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review679 Bupropion XR with overall sexual function [54] at study end (table In bupropion XR trials [45,58] no significant be- VIII).

tween-group differences were observed in bupro- These results were supported by data from a pion XR and placebo recipients in terms of the meta-analysis [69] in which no significant differences proportion of patients with orgasm dysfunction (pri- mary outcome in one study; [58] 13% vs 11% in study between bupropion SR and placebo groups were 1 and 16% vs 8% in study 2),[58] the proportion of observed with respect to the proportion of patients patients with worsening of sexual function (18% vs with treatment-emergent sexual desire disorder (6% 14% in study 1 and 22% vs 16% in study 2), [58] or in vs 6%), sexual arousal disorder (5% vs 6%) or the changes from baseline in CSFQ total or subscale orgasm dysfunction (12% vs 11%) after 8–16 weeks scores after 8 weeks’ therapy (table IX; primary outcome in one study [45] )[45,58] in individual studies, of therapy. [69] In contrast the rates of treatmen- as well as in a pooled analysis of two of these studies emergent sexual desire disorder (17% vs 6%), sexu- (studies 1 and 2 [58] ) [15% vs 9%]. The effect of al arousal disorder (11% vs 6%) and orgasm dys- venlafaxine XR on sexual functioning was also sim- function (37% vs 11%) were significantly (p < 0.01) ilar to that of placebo, with no significant-between higher with SSRI than placebo. group differences in the two groups in CSFQ total or Table IX. Effects of bupropion extended/modified release (BUP XR) on sexual functioning in patients (pts) with moderate to severe major depressive disorder. Adults aged ≥18 y [45,58,59] received BUP XR once daily (od), escitalopram (ESC) od, venlafaxine extended release (VEN XR) od or placebo (PL) for 8–12 wk in large (n >300), randomized, double-blind, multicentre trials (see table VII for dosage details).

Where specified, results were last-observation-carried-forward intent-to-treat, [58] or mixed-model repeated measures analysis. [59] Values at final assessment at end of therapy are reported. Data from two studies (WXL101497 and AK130939) are presented only as part of an abstract and poster [45] Study [duration Treatment (mg/d) Mean change from baseline [baseline values a]b of treatment] [no. of pts] CSFQ total CSFQ subscale scores c score pleasure desire/frequency desire/interest arousal orgasm Comparisons with ESC Clayton et al. [58] BUP XR 300–450 [134] 2.7 † [50.5] 0.5 † [3.0] 0.4 [6.9] 0.4 [9.5] 0.6 [10.8] 0.5 †† [11.5] (study 1) [8 wk] ESC 10–20 [133] 0.2* [52.1] 0.3 [3.2] 0.1 [7.2] 0.1 [9.7] 0.1 [11.4]– 0.6** [11.7] PL [130] 2.4 [51.8] 0.4 [3.2] 0.2 [7.2] 0.3 [9.6] 0.5 [11.2] 0.6 [11.7] Clayton et al. [58] BUP XR 300–450 [129] 2.1 †† [53.8] 0.5 [3.2] 0.2 †† [7.3] 0.4 † [10.4] 0.4 † [11.7] 0.4 †† [12.1] (study 2) [8 wk] ESC 10–20 [133]– 1.1* [53.4] 0.2 [3.3]– 0.3* [7.4]– 0.3 [9.8]– 0.1 [11.6]– 0.8** [12.1] PL [126] 1.3 [52.9] 0.3 [3.3] 0.1 [7.2] 0.2 [9.9] 0.2 [11.4] 0.4 [11.9] Comparisons with VEN XR Thase et al. [59] BUP XR 300–450 [160] 2.0 †d,e 0.5†e 0.2†e 0.3†e 0.5†e 0.1†e [12 wk] VEN XR 150–225 [164]– 1.0 d,e 0.2e – 0.4 e – 0.4 e – 0.2 e – 0.8 e Thase at al. [45] BUP XR 150–300 [187] 6.0 (WXL101497) VEN XR 75–150 [187] 5.2 [8 wk] PL [197] 5.1 Thase at al. [45] BUP XR 150–300 [202] 4.2 (AK130939) VEN XR 150–225 [193] 3.6 [8 wk] PL [186] 3.9 a Baseline values not reported in three studies. [45,59] b Increasing scores indicate improvement.

c In the study by Clayton et al. [58] n = 132–133 in study 1 and 127–129 in study 2 for BUP XR, n = 127–131 and 130–133 for ESC and 126–128 and 124–125 for PL recipients for CSFQ subscale scores.

d Primary outcome measure.

e Estimated from a graph.

CSFQ = Changes in Sexual Functioning Questionnaire; * p < 0.05, ** p < 0.001 vs PL; † p < 0.05, †† p < 0.001 vs active comparator. © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 680Dhillon et al. Bupropion XR subscale scores at week 8 (secondary efficacy mea- Bupropion XR had a more favourable effect on sures; table IX). [45] In contrast, the effect of escitalo- sexual functioning than that of the SSRI escitalo- pram therapy on sexual functioning was generally pram, as indicated by significantly fewer (p < 0.05) worse than that of placebo, as indicated by more bupropion XR than escitalopram recipients exper- (p < 0.01) patients experiencing orgasm dysfunction iencing orgasm dysfunction (primary outcome; 13% with escitalopram than placebo at week 8 (32% vs vs 32% in study 1; 16% vs 29% in study 2) or 11% in study 1; 29% vs 8% in study 2) and by a worsened sexual functioning (18% vs 37% in study significant decrease from baseline in CSFQ total and 1; 22% vs 34% in study 2) at week 8. [58] The relative some subscale scores with escitalopram relative to risks of treatment-emergent orgasm dysfunction placebo in studies 1 and 2 (table IX). These results with bupropion XR versus placebo were 1.2 and 2.0 were supported by the pooled analysis of these stud- in studies 1 and 2, whereas the relative risks with ies. [58] escitalopram versus placebo were 2.9 and 3.6. [58] A 5.4.2 Comparisons with SSRIs and an SNRI significant improvement from baseline in the CSFQ Bupropion SR and XR had a more favourable total and some subscale scores was also observed effect on sexual functioning than the SSRIs ser- with bupropion XR relative to escitalopram therapy traline, [52,53,74] fluoxetine [54] and escitalopram, [58] as at week 8 in studies 1 and 2 (table IX). [58] These well as the SNRI venlafaxine XR in one study [59] results were supported by the pooled analysis of where the primary outcome measure was changes both studies. [58] from baseline in sexual functioning, but not in two Bupropion XR had a more favourable effect on other studies [45] where the assessment of sexual sexual functioning than the SNRI venlafaxine XR in functioning was a secondary outcome measure.

one study which assessed sexual function as the primary outcome measure (mean change from base- Bupropion SR line in CSFQ total scores). [59] These data were sup- The incidence of sexual desire disorder and or- ported by data from a large observational study in gasm dysfunction was significantly lower, and the >6000 adult outpatients receiving antidepressant proportion of patients expressing overall satisfaction monotherapy (see section 7).

[75] However, in two with sexual functioning was significantly higher other studies where sexual function was assessed as with bupropion SR than sertraline [52,53,74] or fluoxe- a secondary outcome measure, [45] there were no tine [54] in 6- to 16-week trials (table VIII). The significant differences between the two treatment incidence of sexual arousal disorder was generally groups (table IX).

similar with bupropion SR and sertraline [52,53] or fluoxetine [54] therapy; however, in one study the 5.5 Bodyweight incidence was significantly lower with bupropion relative to sertraline therapy. [74] Twenty eight percent of bupropion IR recipients experienced a weight loss of >2.3 kg (>5 lb), an Data from individual studies were supported by a incidence approximately twice that observed in pa- meta-analysis, [73] which showed that the risk of ex- tients with MDD receiving TCA therapy or placebo periencing sexual desire disorder (0.65 [95% CI (patient numbers and age group not specified). [7] In 0.51, 0.84]), sexual arousal disorder (risk ratio [RR] terms of weight gain, 9.4% of patients receiving 0.46 [95% CI 0.26, 0.83]) or orgasm dysfunction bupropion IR compared with 35% of those receiving (RR 0.22 [95% CI 0.12, 0.40]) was lower with TCAs reported an increase in weight. [7] bupropion SR than with the SSRIs (sertraline or fluoxetine) after 8–16 weeks of therapy. Similarly, Similarly, 14% and 19% of bupropion SR another meta-analysis [69] showed that significantly 300 mg/day (n = 339) or 400 mg/day (n = 112) and fewer (p < 0.001) patients receiving bupropion SR 6% of placebo (n = 347) recipients reported a weight than SSRIs (sertraline or fluoxetine) had treatment- loss of >2.3 kg, and 3% and 2% of bupropion SR emergent sexual desire disorder (6% vs 17%), sexu- 300 or 400 mg/day and 4% of placebo recipients al arousal disorder (5% vs 11%) or orgasm dysfunc- experienced a weight gain of >2.3 kg in placebo- tion (12% vs 37%) after 8–16 weeks of therapy. controlled trials in patients with MDD (age group © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review681 not specified). [8] In a long-term relapse-prevention baseline in these parameters were observed in study, no clinically significant weight loss was ob- bupropion SR 300 mg/day or placebo recipients served in bupropion SR 300 mg/day or placebo after 52 weeks of therapy in a relapse-prevention recipients after 52 weeks of therapy; however, one trial in adults with MDD. [56] patient withdrew from the study because of a weight In bupropion XR studies, the mean changes from loss of ≈7.8 kg (≈17.2 lb), which may have been baseline to termination of therapy in systolic (– 0.4 to related to study medication. [56] ≤1.3 mmHg) and diastolic blood pressure A weight loss of ≥2.5 kg (≥5.5 lb) was observed (≤1.1 mmHg) and heart rate (– 0.6 to ≤1.3 beats per in 18% of bupropion XR recipients compared with minute [bpm]) were small in bupropion XR, escita- 15% of escitalopram, 12% of venlafaxine XR and lopram, venlafaxine XR and placebo recipients in a 8% of placebo recipients, and a weight gain of pooled analysis of 8-week trials in patients with ≥2.5 kg was observed in 9% of bupropion XR MDD. [70] Increases of potential concern in systolic compared with 12% of escitalopram, 11% of venla- blood pressure (defined as ≥20 mmHg) occurred in faxine XR and 14% of placebo recipients in a pooled 12%, 10%, 15% and 11%, and in diastolic blood analysis of >2200 adults. [70] pressure (defined as ≥15 mmHg) occurred in 12%, 8%, 13% and 9% of bupropion XR, escitalopram, venlafaxine XR and placebo recipients, respective- 5.6 Cardiovascular Events ly; an increase in heart rate of potential concern (defined as ≥120 bpm and an increase of ≥15 bpm) Hypertension, which in some patients was severe was observed in <1% of patients in any group. [70] and required acute treatment, was reported with the Decreases of potential concern in systolic (defined use of bupropion SR alone or in combination with as ≤90 mmHg and a decrease of ≥20 mmHg) or nicotine replacement therapy (not the focus of this diastolic (defined as ≤50 mmHg and decrease of review) in clinical practice, irrespective of whether ≥15 mmHg) blood pressure occurred in <2% of or not patients had pre-existing hypertension. [9] The bupropion XR, escitalopram, venlafaxine XR and incidence of treatment-emergent hypertension in pa- placebo recipients; similarly, decreases of potential tients receiving bupropion SR alone was 2.5% com- concern in heart rate (defined as ≤50 bpm and de- pared with 6.1%, 1.6% and 3.1% in those receiving crease of ≥15 bpm) occurred in <1% of patients in bupropion SR plus nicotine transdermal system, any group. [70] nicotine transdermal system alone or placebo in a In the same pooled analysis, sustained (over three study comparing these options as aids to smoking consecutive visits) increases in systolic blood pres- cessation. [9] sure of ≥15 mmHg from baseline occurred in 3%, The safety of bupropion IR, SR and XR in pa- 2%, 3% and 3%, sustained increases in diastolic tients with recent myocardial infarction or unstable blood pressure of ≥10 mmHg occurred in 6%, 4%, heart disease has not been determined and caution is 9% and 6%, and sustained increases in heart rate of advised when the drugs are administered to these ≥10 bpm occurred in 11%, 7%, 8% and 7% of patients. [7-9] Bupropion (formulation not specified) bupropion XR, escitalopram, venlafaxine XR and was well tolerated in depressed patients who had placebo recipients, respectively. [70] Elderly patients previously developed orthostatic hypertension with MDD receiving bupropion XR or placebo during TCA therapy or who had stable congestive showed generally similar values of potential con- heart failure (n = 36). [9] However, two patients with cern or sustained increases in systolic and diastolic congestive heart failure discontinued therapy be- blood pressure and heart rate. [44] cause of a rise in supine blood pressure. [9] Bupropion SR was not associated with clinically 6. Dosage and Administration significant changes from baseline in heart rate or systolic and diastolic blood pressure in adults with Bupropion is indicated in some European coun- MDD in individual studies [53-55] of 8 weeks’ dura- tries [10] and in the US [7-9] for the treatment of adult tion and in a pooled analysis of 8-week trials. [71] patients with MDD (table X). Bupropion is not Similarly, no clinically significant changes from approved for use in paediatric patients. [7,10] © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 682Dhillon et al. ment should be carefully monitored for adverse ef- fects that indicate increased concentrations of bupropion or its metabolites.

Local manufacturer’s prescribing information should be consulted for full details of contraindica- tions, other precautions and warnings, drug interac- tions, dosage modifications, instructions for switch- ing between bupropion formulations and patient monitoring requirements.

7. Place of Bupropion in the Management of Major Depressive Disorder Often a chronic, recurrent condition, MDD may be associated with considerable impairment of HR- QOL and occupational functioning. [76,77] In the year 2000, MDD was one of the leading causes of global disease burden, accounting for 4.4% of the total disability-adjusted life-years. [78] The main aim of therapy in patients with MDD is to achieve remis- sion of disease and prevent relapse. [5] Current US [5] and UK [77] treatment guidelines recommend the use of antidepressants (e.g. SSRIs, bupropion and venla- Table X. Summary of recommended bupropion (BUP) dosage and administration. [7-10] Local prescribing information should be con- sulted for further details Europe a US Approved formulations XR IR SR XL Initial dosage (mg/d) 150 od 100 bid 150 od b150 od b Day of first dose 29 c 444 increment Dose increment during 150 c 100 d 150 150 titration period (mg/d) Target dosage (mg/d) 150, 300 c od 100 tid 150 bid b300 od b Max. per day (mg) 300 od c 450 tid e400 bid 450 od Max. per dose (mg) 150, 300 c 150 200 450 Dose interval (h)≥24≥6e ≥8≥24 a BUP XR is approved in some European countries (e.g.

Germany, the Netherlands, Iceland, Spain, Norway, Protugal).

b Administration should begin in the morning.

c BUP should be increased to 300 mg/d only if no improvement is seen after 4 wk with 150 mg/d.

d Increase in dose should not exceed 100 mg/d in a 3 d period.

e If BUP IR 100 mg tablets are used, they should be taken four times daily to avoid >150 mg in any one dose, with ≥4 h to the next dose.

bid = twice daily; IR = immediate release; max. = maximum; od = once daily; SR = sustained release; tid = three times daily; XL = modified release; XR = extended release. faxine), with or without psychotherapy, in patients with moderate to severe MDD, [5,77] unless elec- The recommended dosage and administration are troconvulsive therapy is planned. [5] Patients with presented in table X. In order to minimize the risk of mild MDD may also be considered for antidepres- seizures, dosage should not exceed the recommen- sant therapy in some cases, such as in patients who ded maximum and dosage should be increased do not respond to other interventions, [77] have de- gradually (see local prescribing information for pression associated with psychosocial or medical more details). The maximum recommended daily problems, [77] have a prior history of moderate or dose of bupropion XR is 300 mg (Europe) or 450 mg severe depression [77] or who prefer antidepressant (US) [bupropion XL; table X]. Bupropion can be therapy. [5] It is recommended that patients be moni- taken without regard to food, although the SR and tored frequently (every 4–8 weeks [5] or 2–4 weeks in XR tablets should be taken whole. [8-10] the first 3 months and longer intervals thereafter [77] ) In a pooled dataset, treatment with antidepressant for clinical response and tolerability issues and to drugs increased the risk of suicidal ideation and adjust therapy accordingly (e.g. by increasing drug suicidality in paediatric and adolescent patients, and dosages or switching to other antidepressants if ade- is associated with a black box warning in the US quate response is not achieved). [5] Antidepressant prescribing information. [7-9] All patients regardless therapy should be continued for 4–5 [5] or at least of age who are initiated with bupropion should be 6 [77] months after remission is achieved, after which monitored appropriately and observed for signs of time maintenance therapy may be required to pre- clinical worsening, suicidality or unusual changes in vent future recurrences of MDD. [5,77] behaviour.

As noted in section 1, the pharmacotherapeutic In Europe, bupropion is contraindicated in pa- options currently available have generally similar tients with severe hepatic cirrhosis. [10] In the US, antidepressant efficacy, with the choice of therapy extreme caution is advised if this agent is used in determined by factors such as patient preference, the these patients. [7-9] All patients with hepatic impair- adverse event profiles of the drugs and the likeli- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review683 hood of adherence to therapy. [5,79] Because of their In randomized clinical trials of 6–16 weeks’ du- generally more favourable adverse event profiles, ration, bupropion IR [47] and SR [49,52-54] therapies SSRIs and other second-generation antidepressants were effective in the treatment of moderate to severe have replaced the first-generation drugs as first- MDD, with both formulations demonstrating greater line treatment options for moderate to severe improvements from baseline in efficacy measures MDD. [2,5,79] However, there is no gold standard for relative to placebo (sections 4.1 and 4.2.1). In addi- the treatment of MDD, largely because of a lack of tion, bupropion SR was also effective in preventing well designed studies comparing the efficacy of relapse in one 52-week relapse-prevention study in a different antidepressants. [80] similar patient population, [56] although more long- term studies would be helpful in confirming this Bupropion, a second-generation drug, is consid- result.

ered a likely optimal treatment option for patients with moderate to severe MDD. [5] Although the exact However, mixed results were observed with mechanism of action of bupropion is not well under- bupropion XR in six placebo-controlled studies of 8- stood, its effects have been attributed to its ability to or 10-weeks’ duration in adults [45,57,58] and in elder- inhibit norepinephrine and dopamine reuptake (sec- ly [44] patients. Of these, only two [57] studies in adults tion 2). [12] Its mechanism of action is unique among demonstrated greater improvements from baseline currently prescribed antidepressants in that it has no in primary efficacy measures (IDS-IVR-30 or effect on serotonergic, cholinergic, histaminergic MADRS total scores) in bupropion XR relative to and α-adrenergic pathways, [11,12] and this may con- placebo recipients (section 4.3.1). However, in the tribute to a lower incidence of some adverse events trial involving elderly patients, significant reduc- relative to TCAs and SSRIs (section 5). tions from baseline in MADRS total scores in bupropion XR relative to placebo recipients were Bupropion was initially developed as a three- observed in the protocol-defined observed-case or times-daily oral formulation (bupropion IR). [11] The per-protocol analyses and according to the rank ana- IR formulation was followed by the twice-daily lysis of covariance and robust regression analysis (bupropion SR) and once-daily (bupropion XR) oral (these analyses were considered appropriate by in- formulations that were developed to increase conve- dependent experts [31] ) [section 4.3.1]. [44] nience of administration, potentially increasing the likelihood of patient compliance. [11] Indeed, recent It should be noted that the active comparator studies suggest that use of the once-daily formula- escitalopram in two of these studies also showed tion of bupropion XR may improve patient adher- mixed results with respect to the primary efficacy ence to therapy, which, in turn, may decrease the measure (section 4.3.1). [58] However, in two studies likelihood of relapse and may potentially decrease with venlafaxine XR as the active comparator, [45] a depression-associated healthcare costs. [81,82] significantly greater improvement from baseline in the primary efficacy measure (MADRS total scores) Although all three formulations of bupropion was observed with venlafaxine XR relative to place- (IR, SR and XR) are bioequivalent in terms of bo in both studies, whereas a significant improve- systemic exposure to bupropion and its three active ment with bupropion XR was observed in only one metabolites, the SR and XR formulations of bupro- study (section 4.3.1). [45] It has been suggested that pion are associated with longer t max values and a the lack of efficacy observed with bupropion XR decreased number of daily peak plasma levels (sec- relative to placebo in some studies may have been tion 3). Some clinicians suggest that the different because of a high placebo response, which may have pharmacokinetic profiles of the SR and XR com- decreased the ability to differentiate the treatment pared with the IR formulation may be associated groups from placebo. [58] with improved tolerability. [11] Moreover, since the XR formulation is administered in the morning, Some benefits in terms of secondary efficacy plasma bupropion levels are lower during the even- measures, including response and remission rates, ing than with the IR or SR formulations, and it has were observed with bupropion XR relative to place- been suggested that this may be associated with a bo in five of six placebo-controlled efficacy trials lower rate of insomnia. [11] (section 4.3.1). © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 684Dhillon et al. In terms of individual symptoms associated with sion and response rates with both bupropion (IR or MDD, significant improvements from baseline in SR) and SSRI over placebo (section 4.4). There are symptoms of energy, pleasure, interest and insomnia no trials comparing bupropion SR with other com- were observed in bupropion XR relative to placebo monly prescribed antidepressants, including TCAs, recipients in one study (which prospectively includ- SNRIs and other SSRIs (e.g. escitalopram).

ed patients exhibiting these symptoms). [57] Fatigue In studies comparing bupropion XR with the is one of the most common symptoms associated SSRI escitalopram, [58] no significant between-group with MDD occurring in 73–97% of outpatients; differences were observed in terms of the improve- similarly, somnolence has been reported in ≈16% of ment from baseline in primary efficacy measures MDD outpatients. [19] Furthermore, both occur as and secondary efficacy measures (section 4.3.2).

residual symptoms of depression. However, not Similarly, there were no differences between bupro- many studies have assessed the efficacy of antide- pion XR and venlafaxine XR in terms of the prima- pressants in resolving these symptoms. [19] In a meta- ry efficacy measures in two studies (section analysis of six efficacy trials (section 4.4), bupro- 4.3.3); [45,59,67] in one study, [59] more patients pion (SR or XR) was associated with significantly achieved remission with bupropion XR than venla- greater resolution of sleepiness and fatigue relative faxine XR therapy. However, in one study to placebo. [19] These results need to be confirmed in (AK130939), [45,66] venlafaxine XR was significantly direct head-to-head comparisons between bupropion better than bupropion XR in terms of the primary IR, SR or XR and SSRIs.

efficacy measure (section 4.3.3). More studies will Two studies evaluated the effects of bupropion help to establish the efficacy of these two drugs SR [65] or XR [44] relative to placebo on functional and relative to each other. There are no trials comparing HR-QOL measures, which generally improved from bupropion XR with TCAs, SSRIs other than escita- baseline in both adults [65] and elderly patients [44] lopram or SNRIs other than venlafaxine XR and (sections 4.2.1 and 4.3.1). More studies are required direct head-to head comparisons are warranted.

to assess the benefit, relative to placebo, of bupro- Bupropion SR and XR were associated with sig- pion (IR, SR or XR) in terms HR-QOL.

nificantly greater resolution of sleepiness and fa- The efficacy of bupropion IR, SR and XR has tigue relative to treatment with SSRIs (sertraline, been compared with that of several antidepressants, paroxetine or escitalopram) according to results including TCAs, SSRIs and an SNRI, in randomized from a meta-analysis. [19] studies of 6–16 weeks’ duration in patients with As noted earlier in this section, only two studies moderate to severe MDD.

(one placebo-controlled [44] and the other active-con- Bupropion IR was as effective as the SSRI fluox- trolled [55] ) demonstrated the efficacy of bupropion etine, [48] the TCAs nortriptyline, [60] amitriptyline [46] XR versus placebo in adults [44] and that of bupro- and doxepin, [61] and the atypical antidepressant tra- pion SR versus paroxetine in elderly patients with zodone [50] in reducing symptoms of depression and MDD. [55] anxiety as assessed by several efficacy measures Often, no single treatment is uniformly effective (section 4.1). However, these comparisons were for the management of MDD and subsequent inter- based on small trials (<120 patients) that did not ventions with other agents (such as augmenting ther- include a placebo control.

apy with another agent or switching to treatment In studies comparing bupropion SR with SSRIs with another agent) are required. [62] Current treat- (sertraline [51-53] or fluoxetine [54] in adults and the ment guidelines recommend switching to another SSRI paroxetine in elderly patients [55] ), no signif- antidepressant from the same or another class [5,77] (if icant between-group differences were observed in two previous medication trials from the same class terms of the improvement from baseline in symp- were ineffective [5]) or augmenting therapy with an toms of depression as assessed by several efficacy antidepressant from another class in treatment- measures (section 4.2.2). These results from individ- refractory patients.

[5] The efficacy of bupropion as ual trials were supported by results from a meta- an agent to augment SSRI therapy and its efficacy in analysis, [69] which showed benefit in terms of remis- patients switched from prior SSRI therapy was eval- © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review685 uated in a ≤14-week, large, randomized, multicentre response to pain is estimated to be 50% of the response to pain medication. [84] trial (STAR*D). In this trial, in terms of remission rates (primary efficacy measure), bupropion SR was All three formulations of bupropion were gener- as effective as the SSRI sertraline and the SNRI ally well tolerated in patients with moderate to se- venlafaxine XR in patients who were switched from vere MDD (section 5.1). Adverse event-related citalopram therapy because of a lack of remission of withdrawal rates in pooled analyses were 5–11% in symptoms or because they could not tolerate citalo- bupropion IR, SR or XR recipients (section pram. [62] In the same study, bupropion SR was also 5.1). [7,8,70] Overall, the most common treatment- shown to be as effective as the serotonin receptor emergent adverse events reported in bupropion IR, agonist buspirone, with respect to remission rates, SR or XR versus placebo recipients were headache, when used to augment citalopram therapy in a simi- dry mouth and nausea (section 5.1). [7,8,70] Moreover, lar patient population (section 4.2.3). [63] However, bupropion SR and XR were well tolerated in terms there were some benefits with bupropion SR relative of sexual functioning (section 5.4.1). Bupropion SR to buspirone therapy as demonstrated by a greater was also well tolerated with long-term use in a 52-week relapse-prevention study (section 5.1). [56] reduction from baseline in QIDS-SR-16 score, a lower QIDS-SR-16 score at study end (section 4.2.3; Most adverse events associated with bupropion secondary efficacy measures) and a lower rate of SR [71] or XR [45,57] therapy were mild to moderate in discontinuation due to intolerance with bupropion severity (section 5.1). However, there is a dose- SR at study end (section 5.3.4). [63] dependent risk of seizures (0.4% with bupropion IR 300–450 mg/day; 0.1% with bupropion SR Although many antidepressants have demonstra- 100–300 mg/day, increasing to 0.4% with bupro- ted efficacy in the treatment of MDD relative to pion SR 400 mg/day; 0.1% with bupropion XR placebo, there has been recent debate in literature ≤450 mg/day) associated with the use of bupropion regarding the outcome of clinical trials involving IR, SR or XR (section 5.2.1). [7,8,10] SSRIs are asso- these agents. [83,84] A recent meta-analysis of fully ciated with a seizure incidence of approximately published and US FDA-registered studies involving 0.1%. [11] Although the effect of bupropion IR, SR some antidepressants (SSRIs, SNRIs and atypical and XR on suicidality is not clear, it is recommen- antidepressants) suggested that the effect sizes re- ded that patients should be monitored closely for ported in published trials were higher than those clinical worsening, suicidality or unusual changes in derived from FDA reviews, which may lead to un- behaviour (section 5.2.2). [9] realistic estimates of drug efficacy and alter their In general, the effects of bupropion IR, SR and apparent risk-benefit ratio. [83] The authors point out XR on vital signs (systolic and diastolic blood pres- that although each drug when subjected to meta- sure and heart rate) were small, although some analysis was superior to placebo, the magnitude of changes with bupropion XR were of potential con- superiority over placebo was less when unpublished cern or were sustained during therapy (section 5.6).

data were included in the analysis. [83] Another meta- In clinical practice, cases of hypertension, in some analysis (involving SSRI, SNRI and atyptical anti- cases severe and requiring acute treatment, have depressants) suggested that antidepressants may also been reported with the use of bupropion SR produce clinically significant benefit only in the alone or in combination with nicotine replacement most severely depressed patients, but not in those therapy as an aid to smoking cessation (not the focus with moderate to very severe MDD. The correlation of this review) irrespective of whether or not pa- between initial severity of disease and antidepres- tients had pre-existing hypertension (section 5.6). [9] sant efficacy may be attributed to decreased respon- siveness to placebo in patients with very severe Although bupropion (IR, SR and XR) is general- symptoms, rather than increased responsiveness to ly as well tolerated as other antidepressants (section antidepressant therapy. [84] The placebo response in 5), given bupropion’s lack of serotonergic, choliner- these trials was 80% of the improvement observed gic, histaminergic, α-adrenergic, and dopaminergic with antidepressant therapy; in comparison, placebo activity (see section 2), its adverse event profile is © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) 686Dhillon et al.

likely to differ somewhat from that of other antide- defined subpopulation, which excluded patients pressants. likely to have predisposing factors for sexual dys- function, the odds of experiencing sexual dysfunc- Somnolence is one of the more common adverse tion were 4- to 6-fold higher with SSRIs or venlafax- events associated with the use of antidepressants. [85] ine XR than bupropion XR. [75] Direct head-to-head The incidence of somnolence with bupropion IR or comparative trials between bupropion IR and XR SR was lower [50,60,61,69] than with some TCAs [60,61] and other commonly prescribed SSRIs and SNRIs (section 5.3.1) or SSRIs (section 5.3.3), [69] as well as are required.

the atypical antidepressant trazodone (section 5.3.2) [50] On the other hand, the incidence of dry Weight gain is one of the major reasons for mouth was higher [69] with bupropion IR or SR than noncompliance with TCA therapy. [85] Bupropion with some SSRIs (section 5.3.3), [69] but lower than (IR, SR and XR) is also associated with an increase that observed with some TCAs (section 5.3.1). [60,61] in weight gain of >2.3 kg (section 5.5); [7,70] however, the incidence of weight gain was ≈4-fold lower with Sexual dysfunction is frequently (incidence bupropion IR than with TCAs (section 5.5). [7] 40–50%) associated with the use of SSRIs. [11] Im- Bupropion (IR, SR and XR) was also associated portantly, bupropion SR and XR had a more favou- with weight loss of > 2.3 kg (section 5.5); [7,70] how- rable effect on sexual functioning than some SSRIs ever, the incidence of weight loss with bupropion IR in clinical trials. [51-54,59,74] The incidence of sexual was approximately twice that observed with adverse events was lower and patient satisfaction TCAs. [7] No clinically significant changes in weight higher with bupropion SR than the SSRIs ser- were observed in bupropion SR or placebo recipi- traline [51-53,74,75] and fluoxetine [54] (section 5.4.2).

ents after 52 weeks of long-term therapy (section These results were supported by a meta-analysis, [69] 5.5). [56] which showed that fewer patients receiving bupro- pion SR than the SSRIs (sertraline or fluoxetine) had In conclusion, all three oral formulations of treatment-emergent sexual desire disorder, sexual bupropion (IR, SR and XR) are bioequivalent in arousal disorder or orgasm dysfunction. Similarly, terms of systemic exposure to bupropion. Oral the incidence of orgasm dysfunction was lower with three-times-daily bupropion IR was effective and bupropion XR than the SSRI escitalopram (primary generally well tolerated in the treatment of MDD. It outcome measure; section 5.4.2). [58] Bupropion XR was as efficacious and as well tolerated as some had a more favourable effect on sexual functioning TCAs and the SSRI fluoxetine. Moreover, it was than the SNRI venlafaxine XR in terms of the prima- associated with less somnolence and weight gain ry outcome measure (CSFQ total scores) in one than some TCAs. Twice-daily bupropion SR was study (section 5.4.2). [59] However, in two other stud- also efficacious and generally well tolerated in the ies where sexual function was assessed as a secon- treatment of MDD. It was as effective as and had a dary outcome measure, [45] there were no significant generally similar tolerability profile to some SSRIs, differences between the two treatment groups (table but had the advantage of less somnolence and sexual IX). More comparative trials with bupropion XR dysfunction. The efficacy of bupropion XR in terms and venlafaxine XR are required to establish their of primary efficacy measures was established in two effects on sexual functioning.

of six well designed placebo-controlled studies in The advantage of bupropion IR or SR over SSRI patients with MDD. Bupropion XR also demonstra- (including sertraline, paroxetine and citalopram) or ted efficacy in terms of some secondary outcomes in SNRI (venlafaxine or venlafaxine XR) therapy was five of these studies. Additionally, bupropion XR also observed in a cross-sectional, observational was similar, in terms of the primary efficacy out- study involving >6000 adult outpatients receiving comes, to the SSRI escitalopram in two placebo- antidepressant monotherapy, [75] where the propor- controlled trials and to the SNRI venlafaxine XR in tion of patients with sexual dysfunction was 22% two trials (one of which was placebo-controlled), with bupropion IR and 25% with bupropion SR but not in a third placebo-controlled trial where compared with 36–43% with SSRIs, venlafaxine venlafaxine XR was better than bupropion XR. It XR or mirtazapine. [75] Moreover, in a prospectively was generally as well tolerated as escitalopram and © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5) Bupropion: A Review687 nefazodone, bupropion. J Affect Disord 1998 Dec; 51 (3): venlafaxine XR, but was associated with less sexual 237-54 dysfunction than escitalopram. Available clinical 14. Argyelan M, Szabo Z, Kanyo B, et al. Dopamine transporter availability in medication free and in bupropion treated depres- data suggest that bupropion is an effective and gen- sion: a 99mTc-TRODAT-1 SPECT study. J Affect Disord erally well tolerated option in the treatment of 2005 Dec; 89 (1-3): 115-23 MDD, with the newer formulations having the ad- 15. Meyer JH, Goulding VS, Wilson AA, et al. Bupropion occupan- cy of the dopamine transporter is low during clinical treatment. vantage of reduced frequency of daily administra- Psychopharmacology (Berl) 2002 Aug; 163 (1): 102-5 tion. 16. Learned-Coughlin SM, Bergstr¨ om M, Savitcheva I, et al. In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry Disclosure 2003 Oct 15; 54 (8): 800-5 17. Damaj MI, Carroll FI, Eaton JB, et al. Enantioselective effects The preparation of this review was not supported by any of hydroxy metabolites of bupropion on behavior and on external funding. During the peer review process, the manu- function of monoamine transporters and nicotinic receptors. facturer of the agent under review was offered an opportunity Mol Pharmacol 2004 Sep; 66 (3): 675-82 to comment on this article. Changes resulting from comments 18. Fryer JD, Lukas RJ. Noncompetitive functional inhibition at received were made on the basis of scientific and editorial diverse, human nicotinic acetylcholine receptor subtypes by merit. bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther 1999 Jan; 288 (1): 88-92 19. Papakostas GI, Nutt DJ, Hallett LA, et al. Resolution of sleepi- References ness and fatigue in major depressive disorder: a comparison of 1. American Psychiatric Association. Mood disorders. In: Diag- bupropion and the selective serotonin reuptake inhibitors. Biol nostic and statistical manual of mental disorders. Fourth edi- Psychiatry 2006 Dec 15; 60 (12): 1350-5 tion, text revisions. Washington, DC: American Psychiatric 20. Johnston JA, Ascher J, Leadbetter R, et al. Pharmacokinetic Association, 2000: 345-428 optimisation of sustained-release bupropion for smoking ces- 2. Holtzheimer III PE, Nemeroff CB. Advances in the treatment of sation. Drugs 2002; 62 Suppl. 2: 11-24 depression. NeuroRx 2006 Jan; 3 (1): 42-56 21. Ott GE, Rao U, Lin KM, et al. Effect of treatment with bupro- 3. Kessler RC, Berglund P, Demler O, et al. The epidemiology of pion on EEG sleep: relationship to antidepressant response. Int major depressive disorder: results from the National Comor- J Neuropsychopharmacol 2004 Sep; 7 (3): 275-81 bidity Survey Replication (NCS-R). JAMA 2003 Jun 18; 289 22. Ott GE, Rao U, Nuccio I, et al. Effect of bupropion-SR on REM (23): 3095-105 sleep: relationship to antidepressant response. Psychopharma- 4. Alonso J, Angermeyer MC, Bernert S, et al. Prevalence of cology (Berl) 2002 Dec; 165 (1): 29-36 mental disorders in Europe: results from the European Study of 23. Nofzinger 3rd EA, Reynolds CF, Thase ME, et al. REM sleep the Epidemiology of Mental Disorders (ESEMeD) project.

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461-71 E-mail: [email protected] © 2008 Adis Data Information BV. All rights reserved.Drugs 2008; 68 (5)