Resolution of Sleepiness and Fatigue in Major Depressive Disorder: A Comparison of Bupropion and the Selective Serotonin Reuptake Inhibitors

Resolution of Sleepiness and Fatigue in Major Depressive Disorder: A Comparison of Bupropion and the Selective Serotonin Reuptake Inhibitors George I. Papakostas, David J. Nutt, Lindsay A. Hallett, Vivian L. Tucker, Alok Krishen, and Maurizio Fava Background: The purpose of this study was to examine whether the treatment of major depressive disorder (MDD) with the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion results in a greater resolution of sleepiness and fatigue than with the selective serotonin reuptake inhibitors (SSRIs). Methods: Six double-blind, randomized clinical trials comparing bupropion (n ⫽ 662) with an SSRI (n ⫽ 655) for the treatment of MDD were pooled. Hypersomnia scores were defined as the sum of scores of the Hamilton Depression Rating Scale (HDRS) items #22, 23, and 24. Fatigue scores were defined as the score of HDRS item #13. Results: There was a greater improvement in hypersomnia scores among bupropion-treated than SSRI-treated (p ⬍ .0001) or placebo-treated patients (p ⫽ .0008). There was also a greater improvement in fatigue scores among bupropion-treated (p ⬍ .0001) and SSRI-treated (p ⫽ .0005) than placebo-treated patients as well as a greater improvement in fatigue scores among bupropiontreated than SSRI-treated patients (p ⫽ .0078). Fewer bupropion-remitters than SSRI-remitters experienced residual hypersomnia (20.5% vs. 32.1%; p ⫽ .0014) or residual fatigue (19.5% vs. 30.2%; p ⫽ .0020). Conclusion: Treatment of MDD with the NDRI bupropion resulted in a greater resolution of sleepiness and fatigue than SSRIs treatment. Although preliminary, these results warrant prospectively designed studies examining potential differences between bupropion and the SSRIs on these specific depressive symptoms. Key Words: Sleepiness, fatigue, bupropion, SSRIs, MDD, treatment

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t has been estimated that as many as one-half of all patients with major depressive disorder (MDD) do not experience sufficient symptom improvement despite several adequate trials of antidepressant drugs (Fava and Davidson 1996; Petersen et al 2005), with most patients taking a selective serotonin reuptake inhibitor (SSRI) as their initial treatment (Petersen et al 2002). To make matters worse, among those who remit, residual symptoms are common (Nierenberg et al 1999) and are associated with impaired psychosocial functioning (Papakostas et al 2004; Simon et al 2000) and increased relapse rates (Paykel et al 1995). Until recently, known differences among antidepressant drugs were generally limited to aspects of safety and tolerability (Papakostas and Fava 2005). However, over the past few years, a number of studies have emerged suggesting that there might be differences among antidepressant classes in their ability to resolve specific symptoms of depression (Fava et al, unpublished data, 2005; Goldstein et al 2004; Winokur et al 2005). Fatigue is among the most common symptoms of MDD, present in anywhere from 73% to 97% of outpatients (Baker et al 1971; Maurice-Tison et al 1998; Tylee et al 1999). In fact, in a large Pan-European survey of adults who had experienced depression within the past 6 months, almost as many patients complained of fatigue (73%) as low mood (79%) (Tylee et al 1999). In addition, fatigue was reported as the second-most common residual depressive symptom among fluoxetine-remitFrom the Depression Clinical and Research Program (GIP, LAH, MF), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Psychopharmacology Unit (DJN), University of Bristol, Bristol, United Kingdom; and GlaxoSmithKline (VLT, AK), Research Triangle Park, Durham, North Carolina. Address reprint requests to George I. Papakostas, M.D., Massachusetts General Hospital, Depression Clinical and Research Program, Harvard Medical School, Department of Psychiatry, 15 Parkman Street, WACC 812, Boston, MA 02114; E-mail: [email protected]. Received November 9, 2005; revised June 6, 2006; accepted June 8, 2006.

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ters in one study (Nierenberg et al 1999). The presence of fatigue has also been identified as a risk factor predictive of a chronic course for depressive illness (Moos and Cronkite 1999). Although hypersomnia, or excessive sleepiness, is not as common as fatigue in MDD, it has been reported to be present in approximately one in six MDD outpatients (Horwath et al 1992; Posternak and Zimmerman 2001) and in as many as one in three outpatients with atypical MDD (Posternak and Zimmerman 2001). Interestingly enough, as many as 70% (21 of 30) of MDD patients who presented with hypersomnia in one study continued to complain of hypersomnia after remission of symptoms during treatment with fluoxetine (Worthington et al 1995). Unfortunately, however, even though both fatigue and hypersomnia feature prominently as residual symptoms of depression (Fava 2003, 2004), to date, there is a paucity of studies addressing the relative efficacy of antidepressant drugs in resolving fatigue and sleepiness in MDD (Demyttenaire et al 2005). Bupropion hydrochloride, available in the United States for the treatment of depression since 1989 (Fava et al 2005), is a norepinephrine and dopamine reuptake inhibitor (NDRI) with no clinically significant affinity for the serotonergic transporter or the serotonergic, cholinergic, adrenergic, or histaminergic receptors (Ascher et al 1995). To date, published studies suggest that bupropion is as effective as the SSRIs in the overall treatment of MDD (Thase et al 2005), as effective as the SSRIs in the treatment of anxious symptoms of depression (Trivedi et al 2001), and as effective as the SSRIs in the overall treatment of depression regardless of the degree of anxiety at baseline (Rush et al 2001a, 2001b). However, it is unclear whether the treatment of MDD with bupropion results in greater resolution of particular symptoms of depression than the SSRI. Although the biological bases of excessive sleepiness and fatigue in patients with MDD have not been fully elucidated, a number of studies suggest that the neurotransmitters dopamine and norepinephrine play a key role in the pathophysiology of these symptoms (Stahl et al 2003). Therefore, the purpose of the present work was to examine whether the treatment of MDD with the NDRI bupropion results in a greater resolution of sleepiness and fatigue than the SSRIs. BIOL PSYCHIATRY 2006;60:1350 –1355 © 2006 Society of Biological Psychiatry

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Methods and Materials The present work involved pooling individual patient data from six double-blind, randomized clinical trials sponsored by GlaxoSmithKline (Research Triangle Park, North Carolina) comparing bupropion with an SSRI for the treatment of MDD that also included outcome measures for both hypersomnia and fatigue. Although to date (October 2005) a total of 10 studies sponsored by GlaxoSmithKline comparing bupropion with an SSRI for the treatment of MDD have been conducted, 4 of these studies were excluded from the pooled analysis because they did not include Hamilton Depression Rating Scale (HDRS- Hamilton 1960) versions which also measure hypersomnia (i.e., 17- or 21rather than 24-, 28- or 31-item versions of the HDRS were used in those trials). Among the six studies pooled, three used sertraline, one used paroxetine, and two used escitalopram as the SSRI comparator (see Table 1). To our knowledge, studies comparing bupropion with the SSRIs for MDD sponsored by sources other than GlaxoSmithKline have not been conducted. Therefore, to the best of our knowledge, the present analysis is all-inclusive. All six studies included in the present analysis were conducted in accordance with guidelines set by the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (2005), including the administration of institutional review board-approved written informed consent. All patients met criteria for MDD as defined in DSM-IV, and all studies included a 1-week screening phase preceding the double-blind phase. Characteristics of these trials are listed in Table 1.

Definitions and Efficacy Assessments An intent-to-treat (ITT) analysis of all patients randomized to treatment with the last available observation carried forward (LOCF) was applied in the present analyses. Clinical response was defined as a 50% or greater decrease from baseline to end point in 17-item HDRS (HDRS-17) total score. Remission was defined as an HDRS-17 total score ⱕ 7 at end point. Hypersomnia score was defined as the sum of scores of HDRS items #22 (going to bed early), 23 (oversleeping in AM), and 24 (daytime napping). Fatigue score was defined as the score of HDRS item #13. Improvement of a symptom (hypersomnia, fatigue) was defined as the change in scores for that symptom from baseline to end point. Resolution of a symptom was defined as an end point score of 0, whereas residual symptomatology was defined as an end point score ⬎ 0. To reduce the likelihood of chance findings, these definitions were strictly agreed upon by the principal author and the principal biostatistician of the manuscript a priori. Statistical Tests To compare the degree of improvement of hypersomnia and fatigue symptoms between bupropion-, SSRI-, and placebotreated groups, Cochran-Mantel-Haenszel (CMH) row-meanscore tests for the change in each symptom (hypersomnia, fatigue), controlling for baseline level of severity of that symptom, were conducted. Similarly, CMH row-mean-score tests for the severity of each symptom at end point (hypersomnia, fatigue scores) among treatment-remitters were conducted to compare

Table 1. Studies Pooled and Excluded n

Baseline Severity for Inclusion

Included Studies Kavoussi et al 1997

248

HDRS21 ⬎ 17

Croft et al 1999

360

HDRS21 ⬎ 17

Coleman et al 1999

364

HDRS21 ⬎ 17

Weihs et al 2000

100

HDRS21 ⬎ 17

Clayton et al 2006

368

HDRS17 ⬎ 18

Clayton et al 2006

397

HDRS17 ⬎ 18

Excluded Studies Feighner et al 1991

123

HDRS21 ⬎ 19

Unpublisheda

467

HDRS21 ⬎ 19

Coleman et al 2001

456

HDRS21 ⬎ 19

Kennedy et al 2006

140

Trial

Dose mg (mean) Forced Titration

Duration (weeks)

Bupropion SR Sertraline Bupropion SR Sertraline Placebo Bupropion SR Sertraline Placebo Bupropion SR Paroxetine Bupropion XL Escitalopram Placebo Bupropion XL Escitalopram Placebo

100–300 (224) 50–200 (104) 150–400 (293) 50–200 (121)

16

150–400 (290) 50–200 (107)

8

100–300 (199) 10–40 (22) 300–450 (308) 10–20 (13)

6

300–450 (322) 10–20 (13)

8

Bupropion Fluoxetine Bupropion SR Fluoxetine Placebo Bupropion SR Fluoxetine Placebo Bupropion SR Paroxetine

225–450 (338) 20–80 (26) 150–400 (282) 20–60 (28)

6

Treatments

8

8

8

150–400 (289) 20–60 (30)

8

150–300 20–40

8

a Data on file. GlaxoSmithKline, Research Triangle Park, North Carolina. HDRS, Hamilton Depression Rating Scale; SR, sustained release; XL, extended release.

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Table 2. Baseline Characteristics (ITT) Variable

Bupropion

SSRIs

Placebo

n Age (SD) % women (n) HDRS17 Scores (SD) Hypersomnia Scores (SD) Fatigue Scores (SD)

662 39.8 (13.8) 54.3 (360) 22.9 (3.7) 1.7 (1.7) 1.8 (0.4)

655 39.7 (14.0) 53.4 (350) 22.8 (3.7) 1.8 (1.8) 1.8 (0.4)

489 37.2 (11.0) 57.0 (279) 22.6 (3.6) 1.9 (1.7) 1.8 (0.4)

ITT, intent-to-treat; SSRI, selective serotonin reuptake inhibitor; HDRS, Hamilton Depression Rating Scale.

the degree of residual symptomatology between bupropion and SSRIs. The CMH test was chosen because it is the most commonly used non-parameteric, generalized procedure for comparing treatment groups on ordinal or categorical response variables. To reduce the likelihood of chance findings, these statistical tests were strictly agreed upon by the principal author and the principal biostatistician of the manuscript a priori. In addition, the following analyses were defined as primary, a priori: 1) comparing the degree of resolution of fatigue between bupropion and the SSRIs in the ITT population, 2) comparing the degree of resolution of sleepiness between bupropion and the SSRIs in the ITT population, 3) comparing the proportion of bupropion and SSRI remitters with residual fatigue, 4) comparing the proportion of bupropion and SSRI remitters with residual sleepiness. The inflation in Type I error due to multiplicity of testing of the primary analyses was controlled with the Bonferroni method (Bonferroni 1935, 1936). Specifically, the ␣-level for the individual tests was set at .05 (two-tailed), divided by the number of primary analyses performed. Therefore, given a total of 4 primary analyses, statistical significance was set at .05 of 4 or .0125 (two-tailed) for each test. For all secondary analyses, statistical significance was set at ␣ ⫽ .05, two sided.

Results Baseline demographic and clinical characteristics of MDD patients enrolled in the six trials are reported in Table 2. There were no statistically significant differences in any of these variables at baseline between bupropion, SSRI, and placebo groups. The overall remission rates for three treatment groups were: bupropion: 46.5% (308 of 662); SSRIs: 48.7% (324 of 655); and placebo: 34.1% (167 of 489). Treatment with bupropion (p ⬍

Figure 2. Improvement in fatigue (ITT). *p ⬍ .05 versus placebo. **p ⬍ .01 versus SSRIs and placebo. All other analyses p ⬎ .05 (Cochran-Mantel-Haenszel controlling for baseline severity; weeks 2– 6 are observed-case analyses; end point is ITT / last available observation carried forward). HAM-D, Hamilton Depression Rating Scale; SSRI, selective serotonin reuptake inhibitor.

.0001) and the SSRIs (p ⬍ .0001) resulted in greater remission rates than placebo, whereas there was no statistically significant difference in the proportion of remitters between bupropion and the SSRI groups (p ⬎ .05). Pooled Analyses: ITT Sample Controlling for baseline hypersomnia scores, there was a greater improvement in hypersomnia scores in the bupropion (mean ⫾ SEM: ⫺1.1 ⫾ .06) than in the SSRI group (⫺.9 ⫾ .07; p ⬍ .0001) and in the bupropion group than in the placebo group (⫺.9 ⫾ .08; p ⫽ .0008). The difference in the change in hypersomnia scores between the SSRI and placebo groups was not statistically significant (p ⫽ .8161). Figure 1 presents the mean change in hypersomnia scores from baseline during weeks 2, 4, and 6 (observed-case population) and at end point (ITT population) for each treatment group. Controlling for baseline fatigue scores, a greater improvement in fatigue scores was observed in the bupropion (⫺1.1 ⫾ .03; p ⬍ .0001) as well as SSRI (⫺.9 ⫾ .03; p ⫽ .0005) than the placebo-treated group (⫺.8 ⫾ .03). Greater improvement in fatigue scores was also observed in the bupropion-treated than in the SSRI-treated group (p ⫽ .0078). Figure 2 presents the mean change in fatigue scores from baseline during weeks 2, 4, and 6 (observed-case population) and end point (ITT population) for each treatment group. Pooled Analyses: Remitters Demographic and clinical characteristics of bupropion and SSRI remitters are listed in Table 3. There were no statistically significant differences in any of these variables at baseline between bupropion and SSRI remitters. Fewer bupropion remitters experienced residual hypersomnia (20.5%, 63 of 308) than SSRI remitters (32.1%, 104 of 324; p ⫽ .0014). Also, fewer bupropion remitters experienced residual fatigue (19.5%, 60 Table 3. Baseline Characteristics (Remitters)

Figure 1. Improvement in sleepiness (intent-to-treat [ITT]). *p ⫽ .07 versus placebo. **p ⬍ .01 versus SSRIs and placebo. All other analyses p ⬎ .05 (Cochran-Mantel-Haenszel controlling for baseline severity; weeks 2– 6 are observed-case analyses; end point is ITT / last available observation carried forward). HAM-D, Hamilton Depression Rating Scale; SSRI, selective serotonin reuptake inhibitor.

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Variable

Bupropion

SSRIs

n Age (SD) % women (n) HDRS17 Scores (SD) Hypersomnia Scores (SD) Fatigue Scores (SD)

308 39.1 (13.4) 52.9 (163) 22.2 (3.7) 1.7 (1.8) 1.8 (0.4)

324 40.3 (14.1) 52.7 (171) 22.3 (3.6) 1.7 (1.7) 1.8 (0.4)

ITT, intent-to-treat; SSRI, selective serotonin reuptake inhibitor; HDRS, Hamilton Depression Rating Scale.

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Figure 3. Sleepiness and fatigue in major depressive disorder remitters. *p ⫽ .0005 bupropion versus SSRIs. **p ⫽ .0004 bupropion versus SSRIs (Cochran-Mantel-Haenszel controlling for study). SSRI, selective serotonin reuptake inhibitor.

of 308) compared with SSRI remitters (30.2%, 98 of 324) (p ⫽ .0020). These results are depicted graphically in Figure 3.

Discussion The present work adds to a growing literature suggesting differences among antidepressant classes in their ability to resolve specific depressive symptoms (Fava et al 2005; Goldstein et al 2004; Winokur et al 2005). Pooling data from all available double-blind, randomized clinical trials comparing the NDRI bupropion with SSRIs for MDD revealed that treatment with bupropion resulted in a greater resolution of sleepiness and fatigue than SSRI treatment. This was true regardless of the degree of fatigue or sleepiness present immediately before treatment was initiated. Bupropion was more effective than placebo in resolving excessive sleepiness and fatigue as early as week 2, more effective than the SSRIs at resolving excessive sleepiness by week 2, and more effective than the SSRIs at resolving fatigue by week 4 The difference in the resolution of hypersomnia between the SSRIs and placebo did not reach significance at any time-point in the present analysis. Finally, approximately one in five bupropion-remitters compared with nearly one in three SSRI-remitters experienced residual sleepiness and fatigue at end point. Although previous manuscripts comparing bupropion with an SSRI for the treatment of MDD had reported that fewer patients complained of somnolence during treatment with bupropion than with the SSRIs (Fava et al 2005; Thase et al 2005; Trivedi et al 2001), the present analysis is, to our knowledge, the first to examine differences in the efficacy of these agents in resolving these two depressive symptoms. However, we must note several limitations to our work. First, the analysis involved pooling studies comparing bupropion with escitalopram, sertraline, and (to a much lesser extent) paroxetine. Because studies involving fluoxetine and citalopram were not included, conclusions drawn from this study cannot be generalized to all SSRIs. However, it is important to point out that previous works do not suggest any further improvement in fatigue when MDD patients were switched from sertraline, citalopram, or paroxetine to fluoxetine (Joliat et al 2004). In addition, several studies suggest escitalopram to be more effective than citalopram in the treatment of MDD (Burke et al 2002; Lepola et al 2003; Moore et al 2005). Unfortunately, because none of the examined studies involved randomizing to two different SSRIs versus bupropion, it is also not possible to examine whether there are individual differences regarding the effects of the SSRIs on sleepiness and fatigue. Second, only a single and unvalidated measure of sleepiness and fatigue was included in the analysis. Therefore, we could not

confirm or refute these findings with the use of another measure. In addition, the present work involved pooling clinical trials, which typically involve a number of inclusion and exclusion criteria. Hence, it might not be possible to directly extend the findings of this study to groups of patients typically excluded from participating in randomized clinical trials. Furthermore, all but one study included in the analysis were of 6 – 8 weeks in duration. Whether the present findings would extend beyond the acute phase of treatment remains to be determined. Other limitations specifically pertain to the identification of studies to be included in pooled analyses or meta-analyses and include the phenomenon of publication bias as well as the file-drawer phenomenon. Thus, although we included all eligible studies sponsored by GlaxoSmithKline regardless of whether they had been published, it is quite possible that studies sponsored by other sources have been conducted but have not yet been published or presented at major scientific meetings. Furthermore, pooled analyses and meta-analyses involve combining studies of heterogeneous design. In general, a single clinical trial of equivalent statistical power can yield more accurate estimates of a treatment effect. However, trials pooled in the present analysis had many similarities, including a 1-week washout period before randomization, a forced-titration dosing schedule, a comparable baseline depression severity threshold for inclusion, and similar treatment duration. Finally, although the sample size included in the present work was relatively large, it is quite possible that the present findings might be due to chance alone. However, to reduce the likelihood of chance findings, all definitions of outcome and statistical tests were strictly agreed upon by the principal author and the principal biostatistician a priori and a Bonferroni correction was used for all primary analyses. In addition, the range in degree of statistical significance of our primary findings (p ⫽ .0078 to p ⬍ .0001) suggest that the probability of arriving at such findings or findings further in favor of bupropion due to chance alone ranges from ⬍ 1 in 100 to ⬍ 1 in 10,000; hence the probability of all of our primary findings due to chance alone is much smaller than 1 in 10,000.

Conclusion Treatment of MDD with the NDRI bupropion resulted in a greater resolution of sleepiness and fatigue than SSRI treatment. Approximately one in five bupropion-remitters compared with nearly one in three SSRI-remitters experienced residual sleepiness and fatigue at end point. In light of studies linking a greater burden of residual symptoms of MDD with poorer psychosocial functioning and increased relapse rates, future studies should focus on the relationship between the resolution of fatigue and excessive sleepiness, psychosocial functioning and the risk of relapse during the pharmacotherapy of MDD. This work was supported, in part, by National Institute of Mental Health grant K23 MH069629 (to GIP). GIP and DJN have received honoraria from and have served as consultants for GlaxoSmithKline. MF has received research support from Abbott Laboratories, Alkermes, Lichtwer Pharma GmbH, Lorex Pharmaceuticals as well as honoraria from Bayer AG, Biovail Pharmaceuticals, BrainCells, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, EPIX Pharmaceuticals, FabreKramer Pharmaceuticals, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knoll Pharmaceutical Company, Lundbeck, MedAvante, Nutrition 21, PharmaStar, Sepracor, and Somerset Pharmaceuticals. In addition, MF has received both www.sobp.org/journal

1354 BIOL PSYCHIATRY 2006;60:1350 –1355 research support and honoraria from Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals, GlaxoSmithkline, J & J Pharmaceuticals, Novartis, Organon, PamLab, LLC, Pfizer, Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, and WyethAyerst Laboratories. MF owns shares of Compellis and MedAvante. VLT and AK are employees of GlaxoSmithKline. DJN is a consultant for GlaxoSmithKline, Pfizer, Organon, UCB Pharma, Wyeth, Bristol-Myers Squibb, and MSD UK; has received grant/research support from Novartis, GlaxoSmithKline, Organon, UCB Pharma, Pierre Fabre, AstraZeneca, and MSD UK; and has received honoraria from and is a member of the speakers/advisory boards for Wyeth, Organon, and Bristol-Myers Squibb. The authors would like to thank Elizabeth P. Goodale, Pharm. D., for her help and input in the overall coordination of the analysis effort. We would also like to thank Rafe Donahue, Ph.D., from Vanderbilt University School of Medicine and Nathalie Richard, M.S., from GlaxoSmithKline for their input and help with the statistical analysis and Sajida Chughtai, B.S., and Russel Hinkle, B.S., from GlaxoSmithKline for their help with the statistical programming. Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, et al (1995): Bupropion: A review of its mechanism of antidepressant activity. J Clin Psychiatry 56:395– 401. Baker M, Dorzab J, Winokur G, Cadoret RJ (1971): Depressive disease: Classification and clinical characteristics. Compr Psychiatry 12:354 –365. Bonferroni CE (1935): Il calcolo delle assicurazioni su gruppi di teste. In: Studi in Onore del Professore Salvatore Ortu Carboni. Rome, Italy, 13– 60. Bonferroni CE (1936): Teoria statistica delle classi e calcolo delle probabilità. Pubblicazioni del Istituto Superiore di Scienze Economiche e Commerciali di Firenze 8:3– 62. Burke WJ, Gergel I, Bose A (2002): Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 63:331– 336. Clayton AH, Croft HA, Horrigan JP, Wightman DS, Krishen A, Richard NE, Modell JG (2006): Bupropion extended release compared with escitalopram: Effects on sexual functioning and antidepressant efficacy in 2 double-blind, placebo-controlled trials. J Clin Psychiatry 67:736 –746. Coleman CC, Cunningham LA, Foster VJ, Batey SR, Donahue RM, Houser TL, Ascher JA (1999): Sexual dysfunction associated with the treatment of depression: A placebo-controlled comparison of bupropion sustained release and sertraline treatment. Ann Clin Psychiatry 11:205–215. Coleman CC, King BR, Bolden-Watson C, Book MJ, Segraves RT, Richard N, et al (2001): A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine. Clin Ther 23:1040 –1058. Croft H, Settle E Jr., Houser T, Batey SR, Donahue RM, Ascher JA (1999): A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther 21:643– 658. Demyttenaire K, De Fruyt J, Stahl SM (2005): The many faces of fatigue in major depressive disorder. Int J Neuropsychopharmacol 8:93–105. Fava M (2003): Symptoms of fatigue and cognitive/executive dysfunction in major depressive disorder before and after antidepressant treatment. J Clin Psychiatry 64(suppl 14):30 –34. Fava M (2004): Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry. 65(suppl 16):27–32. Fava M, Davidson KG (1996): Definition and epidemiology of treatmentresistant depression. Psychiatr Clin North Am 19:179 –200. Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA (2005): 15 years of clinical experience with bupropion HCl: From bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry 7:106 –113. Feighner JP, Gardner EA, Johnston JA, Batey SR, Khayrallah MA, Ascher JA, Lineberry CG (1991): Double-blind comparison of bupropion and fluoxetine in depressed outpatients. J Clin Psychiatry 52:329 –335.

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