Desvenlafaxine for the treatment of major depressive disorder.

Drug Evaluation

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Desvenlafaxine for the treatment of major depressive disorder 1.

Introduction

2.

Desvenlafaxine

3.

Conclusion

4.

Expert opinion

Susan G Kornstein†, Roger S McIntyre, Michael E Thase & Matthieu Boucher †

Department of Psychiatry and Institute for Women’s Health, Virginia Commonwealth University, Richmond, VA, USA

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability. Areas covered: This review focuses on recent (£ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed. Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit. Keywords: adverse drug event, desvenlafaxine, major depressive disorder, pharmacodynamics, pharmacokinetics, treatment efficacy Expert Opin. Pharmacother. (2014) 15(10):1449-1463

1.

Introduction

Major depressive disorder (MDD) is a chronic and debilitating condition [1-3] with a 12-month prevalence of 1 -- 11% worldwide (7% USA, 4% Europe) and a 3 -- 17% lifetime prevalence (16 -- 17% USA, 13% Europe) [4,5]. Current guidelines for the treatment of depression recommend pharmacotherapy for moderate to severe MDD, with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) or atypical antidepressants as first-line treatment options [6,7]. Although the majority of patients diagnosed with a new episode of depression are prescribed antidepressant drugs [8], guideline-concordant care in MDD is uncommon [9]. To reduce the risk of relapse, continued antidepressant treatment is recommended for at least 4 -- 9 months following acute treatment of a depressive episode [6,7,10]. Long-term (continuation and maintenance) treatment of a year or more is recommended for some patients, such as those who have had three or more prior major depressive episodes or who have chronic MDD, to reduce the risk of recurrence [4,6]. Unmet medical need In a retrospective database analysis of > 134,000 patients prescribed antidepressant drugs, almost one quarter (23%) of the patients required a treatment change (switch or augmentation) during the first 12 months of treatment [11]. Changes in 1.1

10.1517/14656566.2014.923403 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

1449

S. G. Kornstein et al.

Box 1. Drug summary. Drug name Phase Indication Pharmacology Route of administration Chemical structure

Desvenlafaxine (administered as desvenlafaxine succinate) Launched Major depressive disorder Serotonin-norepinephrine reuptake inhibitor Oral CH3 N

CH3 COOH H2O


HO HO

Pivotal trials

COOH

223-WW, 304-US [122], 306-US [64], 308-EU/WW [65], 309-EU [123], 317-US [123], 320-US [124], 332-US [66], 333-EU [67]

antidepressant treatment are often necessary due to poor efficacy [12], as rates of response and remission with antidepressant treatment are low [13,14]. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, > 70% of patients failed to achieve remission in the first treatment step (based on the 17-Item Hamilton Rating Scale for Depression [HAM-D17] total score £ 7) [13]. The cumulative remission rate reported in STAR*D after four sequential treatment steps was reported at 67% [14]. For patients who do achieve remission, residual symptoms often remain after antidepressant treatment. In an assessment of STAR*D patients, 90% of individuals who achieved remission according to the MacArthur criteria [15] reported ongoing residual symptoms including sleep disturbance, changes in weight and appetite, sad mood, poor concentration and decreased energy [16]. Residual symptoms of depression are associated with reduced functioning and quality of life and an increased risk of relapse of depression [16-19]. In randomized withdrawal studies, the estimated probability of relapse for patients prescribed SSRIs and SNRIs ranged from 20 to 28% over 6 -- 12 months of doubleblind treatment (34 -- 52% for placebo) [20-24], and in a systematic review of recurrence risk of MDD in naturalistic cohort studies, rates of recurrence ranged from 21 to 37% during the first year of follow-up, and 42 -- 75% over 5 years [19]. Overview of the market The first-line treatment options for MDD, SSRIs (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), SNRIs (e.g., venlafaxine, duloxetine, desvenlafaxine, levomilnacipran) and atypical antidepressants (e.g., bupropion, mirtazapine, nefazodone, trazodone) are commonly prescribed for patients diagnosed with depression [6-8]. Although antidepressant drug safety and tolerability profiles differ between and within classes, there are several common concerns for patients prescribed antidepressants, including weight gain, effects on sexual function and the potential for drug--drug interactions (DDIs) [25-27]. Further, antidepressant treatment is often 1.2

1450

associated with residual symptoms of depression after acute treatment of a depressive episode. The majority of patients meeting the MacArthur criteria for remission report one or more residual symptoms, including cognitive symptoms, sleep disturbance and lack of energy [28]. Poor tolerability and residual symptoms are both factors leading to poor adherence [29]. Although adherence rates are significantly higher for the newest antidepressant drugs (extended release formulations of bupropion and of SSRIs and SNRIs) compared with first (monoamine oxidase inhibitors, tricyclic antidepressants) and second (immediate release formulations of bupropion and of SSRIs and SNRIs) generation antidepressants, under 35% of patients prescribed the newest antidepressant medications remain adherent to treatment [30]. Desvenlafaxine is among the several new antidepressant drugs, including vortioxetine [31], levomilnacipran [32] and agomelatine [33,34], to recently be approved for the treatment of MDD in the USA [35,36] or Europe [37]. 2.

Desvenlafaxine

Chemistry and pharmacodynamics Desvenlafaxine is administered clinically as a succinate salt monohydrate of O-desmethylvenlafaxine (C16H25NO2; Box 1), the major active metabolite of venlafaxine [38,39]. The oral dose yields equivalent exposure to the (R)- and (S)-desvenlafaxine enantiomers [40]. Desvenlafaxine is an SNRI with selective inhibitory activity of neurotransmitter uptake at the human serotonin (hSERT) and norepinephrine monoamine (hNET) transporters [41]. It has no significant interactions with muscarinic, cholinergic, H1-histaminergic, or a1-adrenergic receptors in vitro, and it lacks significant affinity for any of the numerous other targets tested, including brain/gut peptides, steroids, prostaglandins, growth factors/hormones, ion channels and second messengers [41]. Desvenlafaxine has approximately 10-fold greater activity for hSERT compared with hNET [41]. Whereas venlafaxine is reported to have noradrenergic activity at a high dose 2.1

Expert Opin. Pharmacother. (2014) 15(10)

Desvenlafaxine

Table 1. Pharmacokinetic profile of desvenlafaxine. t1/2 tmax Absolute oral bioavailability Food effect Dose vs concentration relationship Protein binding Major metabolic pathways


Metabolic enzymes inhibited

11 h 7.5 h 80% Not clinically significant Linear and dose-proportional over 100 -- 600 mg/d 30% UGT conjugation; minor CYP 3A4 CYP 2D6 (no significant impact)

CYP: Cytochrome P450; t1/2: Half-life; tmax: Time to peak plasma concentration; UGT: uridine 5’-diphospho-glucuronosyltransferase.

(225 mg/d) but not at a low dose (75 mg/d) using a systemic tyramine pressor response test [42], a possible dose effect on noradrenergic activity has not been investigated for desvenlafaxine. 2.2

Metabolism and pharmacokinetics

exposure increased with increasing disease severity in a study enrolling subjects with chronic renal impairment or end-stage renal disease (ESRD) [49]. A dose adjustment to 50 mg every other day is recommended for patients with severe renal impairment or ESRD [38,39,49]. The PK of desvenlafaxine was also assessed in subjects with hepatic impairment and, consistent with the small role of hepatic enzymes in desvenlafaxine metabolism, no statistically significant effects of hepatic impairment (‡ 50% difference in PK values vs healthy subjects) were observed [50]. However, exposure increased 31 and 35%, and clearance decreased 20 and 35%, respectively, in subjects with Child-Pugh class B and C hepatic impairment [50]. Based on those results, a maximum dose of 100 mg/d is recommended for patients with moderate to severe hepatic impairment [38]. Desvenlafaxine exposure is not affected by CYP 2D6--poor metabolizer status, which has been demonstrated to reduce exposure to the CYP 2D6 substrate venlafaxine [51,52] and to decrease the antidepressant efficacy of venlafaxine [53]. There is no apparent effect of race on desvenlafaxine PK [38,39]. Potential for drug--drug interactions The potential for desvenlafaxine to act as either the victim or perpetrator of DDIs via the CYP system has been assessed in a series of PK studies (Table 2). Results from studies in which desvenlafaxine was coadministered with substrates of CYP 2D6 (desipramine), CYP 3A4 (midazolam) or both isoenzymes (aripiprazole, tamoxifen) indicate that desvenlafaxine has a low potential for clinically significant interactions with other drugs via either of the two pathways: desvenlafaxine showed either no signal or weak interaction, based on US Food and Drug Administration (FDA) definitions [54], with CYP 2D6 and/or CYP 3A4 substrate drugs or the CYP 3A4 inhibitor, ketoconazole [55-60]. In addition, little evidence of desvenlafaxine interaction with the P-glycoprotein transport protein (P-gp), as either a substrate or an inhibitor, has been observed in in vitro and in vivo studies [61-63]. 2.2.1

The metabolism and pharmacokinetics (PK) of desvenlafaxine has been reviewed previously [43], and is summarized here briefly, with a focus on more recent PK studies. The primary metabolic pathway for desvenlafaxine is conjugation to desvenlafaxine O-glucuronide via multiple uridine 5-diphosphate glucuronosyltransferases [44]. Approximately 19% of the desvenlafaxine dose is excreted in urine as the glucuronide metabolite and 46% is excreted unchanged [44]. Desvenlafaxine has little interaction with the hepatic cytochrome P450 (CYP) system; < 5% of the drug is eliminated as the oxidative metabolite N,O-didesmethylvenlafaxine [38-40,44]. CYP3A4 mediates N-demethylation of desvenlafaxine [40,44]. The parent drug, venlafaxine, is metabolized to desvenlafaxine via the CYP2D6 pathway [45], but CYP2D6 is not involved in desvenlafaxine metabolism [44]. The PK profile for desvenlafaxine is summarized in Table 1. Time to peak plasma concentration is 7.5 h after administration (compared with 5.5 h for venlafaxine [46]), and steadystate desvenlafaxine plasma concentrations are achieved after ~ 4 days [38,39] (venlafaxine, 3 days [46]). Single-dose PK has been demonstrated to be linear and dose-proportional over doses ranging from 100 -- 600 mg/d [47] (venlafaxine, linear over the dose range 75 -- 450 mg/d [46]), and multiple-dose accumulation of desvenlafaxine is predictable from the single-dose PK [47]. Small to moderate sex differences in PK that appear to be at least in part due to differences in body weight have been reported, but the differences were not clinically significant and no dose adjustment is considered necessary [48]. Exposure to desvenlafaxine increased with increasing age, consistent with age-related decline in renal function [48]. Although no dose adjustment is specifically recommended on the basis of age alone [48], reduced renal clearance should be considered in dosing for the elderly [49]. Desvenlafaxine

2.3

Clinical efficacy Short-term efficacy

2.3.1

The short-term efficacy and safety of desvenlafaxine for the treatment of MDD have been assessed over the dose range of 10 -- 400 mg/d [64-72]. Early short-term studies assessing 50 -- 400 mg/d doses have been reviewed previously [73], and pooled results from an integrated efficacy analysis of the full set of desvenlafaxine registration trials, including five fixedand four flexible-dose trials, demonstrated efficacy at all doses of 50 mg/d or greater using the primary end point of change from baseline in HAM-D17 total score [74]. In that analysis, no additional efficacy benefit was observed at desvenlafaxine doses higher than 50 mg/d, based on group mean depression scale scores [74]. Remission rates based on HAM-D17 total score ranged from 32% for the 400-mg/d desvenlafaxine dose to 36% for the 50- and 100 mg/d doses (placebo, 23 -- 26%; all p £ 0.012) [74]. Among the eight fixed-dose,


1451


Table 2. Desvenlafaxine potential for drug--drug interactions via the CYP 2D6 and CYP 3A4 pathways. Substrate drug Metabolite CYP 2D6 Desipramine


CYP 3A4 Midazolam CYP 2D6 and CYP 3A4 Tamoxifen Endoxifenz Aripiprazole CYP 3A4 inhibitor Ketoconazole

Desvenlafaxine dose (mg/d)

Interaction* (ratio of AUC means)

Ref.

100 100 400

No interaction (117%) Weak interaction (136%) Weak interaction (190%)

[57] [56] [57]

50 400

Weak interaction (71%) Weak interaction (69%)

[58] [58]

100 100 100

No interaction (101%) No interaction (88%) No interaction (106%)

[60]

400

Weak interaction (143%)

[58]

[59]

Based on FDA criteria: no interaction, ratio of AUC means falls wholly within 80 -- 125%; weak interaction, ratio of AUC means ‡ 125% but < 200%. Active metabolite produced by CYP 2D6--mediated biotransformation of tamoxifen. AUC: Area under the plasma concentration versus time curve; Cmax: Peak plasma concentration. * z

placebo-controlled trials that included a desvenlafaxine 50 mg/d treatment arm that have been completed to date, six showed a statistically significant improvement in depressive symptoms on the primary efficacy end point for the 50 mg/d dose group versus placebo (remission rates: desvenlafaxine 24 -- 40%, placebo 17 -- 32%) [66,67,69-71,75] and two did not [68,72]. It is critical to note that the integrated analysis comparing dose groups was based on data from fixed-dose, clinical trials in which patients were randomly assigned to their dose group without any dosage adjustment for efficacy or tolerability and, therefore, may not generalize to real-life clinical settings. No dose optimization studies have been conducted for desvenlafaxine, and treatment guidelines suggest that individual patients with partial response to antidepressant treatment may respond more fully to higher doses [6,7,73]. The current review includes all Pfizer-sponsored placebocontrolled desvenlafaxine clinical trials of MDD in adults published since 2008, and post hoc subgroup analyses based on their data. The primary results from all completed Phase III and IV, placebo-controlled, desvenlafaxine efficacy and safety trials have been published, except the most recently completed trial, which is currently in press [75], including negative or failed trials [68,72]. These more recent desvenlafaxine clinical trials have focused on lower doses (10 -- 100 mg/d) and examined maintenance of acute-phase efficacy (Table 3). To determine whether 50 mg/d is the lowest effective desvenlafaxine dose, short-term (8-week) efficacy was assessed at 10 and 25 mg/d desvenlafaxine doses in respective studies [69,72]. Both studies also included placebo and desvenlafaxine 50 mg/d arms. In the 10 mg/d study, neither desvenlafaxine dose statistically separated from placebo on the primary efficacy end point [72]. The second study demonstrated desvenlafaxine efficacy at the 50 mg/d dose but not at 25 mg/d (remission rates did not differ significantly from placebo [19%] for either the 50 mg/d [26%] or 25 mg/d [17%] dose group) [69]. Taken 1452

together, the results of those studies demonstrate no evidence for efficacy for treating MDD at desvenlafaxine doses lower than 50 mg/d. The short-term efficacy of the desvenlafaxine 50 and 100 mg/d doses was confirmed in a recent Phase IV, double-blind, placebo-controlled trial (n = 909). The adjusted mean difference (95% CI) was 1.57 (0.44, 2.69; p = 0.006) for desvenlafaxine 50 mg versus placebo and 1.96 (0.84, 3.08; p < 0.001) for desvenlafaxine 100 mg/d versus placebo [75]. Relapse prevention studies: open-label and randomized withdrawal

2.3.2

Four longer-term (6 -- 12 months’ duration), open-label studies of desvenlafaxine (25 -- 400 mg/d) in adults with MDD have been completed [76-79]. One of the studies enrolled elderly patients (‡ 65 years) and another enrolled Japanese patients. The primary objective of each study was the assessment of safety in continuation treatment, but efficacy data collected in the studies indicated that early improvement in HAM-D17 total score from baseline was maintained over 6 -- 12 months of open-label treatment. A significantly longer time to relapse was demonstrated for desvenlafaxine 200 -- 400 mg/d and 50 mg/d versus placebo in separate randomized withdrawal studies [80,81]. In both studies, relapse rates were approximately twice as high for patients receiving placebo (42 and 28%, respectively) compared with patients receiving desvenlafaxine (24 and 14%, respectively) [80,81]. Rates for both desvenlafaxine and placebo were numerically lower in the 50 mg/d study, which used a longer open-label treatment period before randomization, and more stringent response criteria for enrollment in the double-blind phase compared with the higher dose study. Secondary efficacy outcomes Secondary efficacy outcomes collected in desvenlafaxine clinical trials, including symptoms of depression, and functional 2.3.3


Desvenlafaxine

Table 3. Desvenlafaxine clinical trials in adults with major depressive disorder (2008 to present). Ref.

Clinical trial identifier


Short-term, 50 mg/d studies [66] NCT00277823

Study design

Randomized DB, placebo-controlled, fixed dose

[67]

NCT00300378

Randomized DB, placebo-controlled, fixed dose

[68]

NCT00384033

Randomized, DB, placebo- and, comparator-controlled, fixed dose

[69]

NCT00798707

Randomized, DB, placebo-controlled, fixed dose

[72]

NCT00863798

Randomized, DB, placebo-controlled, fixed dose

[71]

NCT01121484

[70]

NCT00824291

[75]

NCT01432457

Randomized, DB, placebo-controlled, fixed dose (peri/postmenopausal women) Randomized, DB, placebo-controlled, fixed dose Randomized, DB, placebo-controlled, fixed dose

Randomized, DB, flexible dose studies [124] NCT00092911 Randomized DB, placebo-controlled, flexible dose [95] NCT00406640 Randomized, DB, comparatorcontrolled, flexible dose (postmenopausal women) [94] NCT00369343 Randomized, DB, placebo-controlled, flexible dose (peri/postmenopausal women) Relapse prevention studies: open-label and randomized withdrawal [77] NCT01309542 10-month, OL extension, flexible dose [78] NCT00452595 12-month, OL, flexible dose [79] NCT00831415 10-month, OL extension, flexible dose (Japanese) [76] NCT00242229 6-month, OL, flexible dose (elderly patients ‡ 65 years) [95] NCT00406640 6-month, DB continuation phase (postmenopausal women; responders) [96] NCT00406640 6-month, OL extension/switch (postmenopausal women; nonresponders) [80] NCT00075257 DB, placebo-controlled, flexible dose, randomized withdrawal [81] NCT00887224 DB, placebo-controlled, fixed dose, randomized withdrawal Discontinuation study [102] NCT01056289 DB, placebo-controlled, fixed dose, randomized discontinuation

Treatment arms

Safety population*

Desvenlafaxine 50 mg/d Desvenlafaxine 100 mg/d Placebo Desvenlafaxine 50 mg/d Desvenlafaxine 100 mg/d Placebo Desvenlafaxine 50 mg/d Desvenlafaxine 100 mg/d Duloxetine 60 mg/d Placebo Desvenlafaxine 25 mg/d Desvenlafaxine 50 mg/d Placebo Desvenlafaxine 10 mg/d Desvenlafaxine 50 mg/d Placebo Desvenlafaxine 50 mg/d Placebo

451

Desvenlafaxine 50 mg/d Placebo Desvenlafaxine 50 mg/d Desvenlafaxine 100 mg/d Placebo

427

Desvenlafaxine 200 -- 400 mg/d Placebo Desvenlafaxine 100 -- 200 mg/d Escitalopram 10 -- 20 mg/d

235

Desvenlafaxine 100 -- 200 mg/d Placebo

381

Desvenlafaxine 200 -- 400 mg/d Desvenlafaxine 200 -- 400 mg/d Desvenlafaxine 25 -- 100 mg/d

1395 104 304

Desvenlafaxine 100 -- 200 mg/d

52

Desvenlafaxine 100 -- 200 mg/d Escitalopram 10 -- 20 mg/d Desvenlafaxine 100 -- 200 mg/d

360 129

Desvenlafaxine 200 -- 400 mg/d Placebo Desvenlafaxine 50 mg/d Placebo

594 375 874 548

Desvenlafaxine 50 mg/d Desvenlafaxine 25 mg/d Placebo

480 (OL) 361 (DB)

485

616

699

673

434

909

595

(OL) (DB) (OL) (DB)

*All randomized patients who took at least one dose of study medication. DB: Double blind; OL: Open label.


1453


Table 4. Desvenlafaxine pooled analyses. Ref.

Analysis

Number of pooled studies

Treatment arms

Analysis N


Efficacy [74]

Efficacy, registration trials

9 studies

[82]

HAM-D17 items

9 studies

[89]

Functional and QOL outcomes

9 studies

[97]

Effect of age and sex on efficacy

9 studies

[83]

Efficacy for anxious symptoms

9 studies

[125]

10 studies

[126]

Functional impairment and depression severity Efficacy for moderate vs severe MDD Predictors of treatment success

6 studies

[84]

Functional improvement

7 studies

[99]

Efficacy in anxious depression

7 studies

[85]

Peri- vs postmenopausal women

2 studies

[98]

Safety and tolerability [100] Safety and tolerability, registration trials [101] Discontinuation symptoms

Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo

6 studies

9 studies

Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo Desvenlafaxine Placebo

10 studies

[109]

Suicidal thoughts and behaviors

9 studies

[106]

Weight change

10 studies

[107]

Weight change

9 studies

50 -- 400 mg/d

2913

50 -- 400 mg/d

2913

50 -- 400 mg/d

2913

50 -- 400 mg/d

2913

50 -- 400 mg/d

2913

50 -- 400 mg/d

3530

50 mg/d

2189

50 mg/d

2274

50 mg/d

2706

50 mg/d

1873

50 or 100 -- 200 mg/d

798

50 -- 400 mg/d

2950

50 -- 400 mg/d

3544

50 -- 400 mg/d

3194

50 -- 400 mg/d

3544

50 and 100 mg/d

4273

HAM-D17: 17-item Hamilton Rating Scale for Depression; OL: Open label; QOL: Quality of life.

and quality of life (QOL) outcomes, have been assessed in pooled analyses of data from multiple placebo-controlled trials (Table 4). In a pooled analysis of the nine short-term, fixed- and flexible-dose desvenlafaxine registration trials (n = 2913, intent-to-treat), desvenlafaxine 50 -- 400 mg/d treatment was associated with significant improvement in 10 of 17 HAM-D17 item scores and 9 of 10 Montgomery A˚sberg Depression Rating Scale (MADRS) item scores versus placebo [82]. Results were similar across desvenlafaxine dose groups. However, treatment with the 50 mg/d dose (n = 314, intent-to-treat) did not significantly improve the suicide item on either scale, although it was significant overall [82]. The 50 mg dose was associated with significant improvement in somatic anxiety, which was not improved overall [82]. In a separate analysis of the same trials, significant improvement compared with placebo was observed in the HAM-D17 anxiety/somatization factor overall and in each desvenlafaxine dose group [83]. Improvement in energy, as measured by HAM-D17 psychomotor retardation and the MADRS 1454

lassitude item, was observed in a pooled analysis of seven double-blind, placebo-controlled fixed-dose studies of desvenlafaxine 50 mg/d in MDD [84]. Functional and QOL outcomes have been assessed in desvenlafaxine trials using the Sheehan Disability Scale (SDS) [85], 5-item World Health Organization Well-Being Index (WHO-5) [86], Work Productivity and Activity Impairment (WPAI) scale [87] and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) [88]. In a pooled analysis of eight of the nine registration trials (excluding a Phase II trial in which functional end points were not collected), the overall pooled population achieved significant improvement compared with placebo in SDS and WHO-5 total scores and all item scores for each scale [89]. In seven pooled desvenlafaxine 50 mg trials, desvenlafaxine treatment was associated with significantly greater improvement in SDS total score compared with placebo (adjusted mean difference [95% CI], --1.71 [--2.29, --1.14]; p < 0.0001), and the proportions of patients achieving functional response (SDS total score £ 12) and



Desvenlafaxine

functional remission (SDS total score < 7) were significantly greater for the desvenlafaxine group (49, 23%) compared with placebo (38, 17%) [84]. Functional and QOL end points were further examined in a 12-week study of employed MDD patients with functional impairment at baseline (n = 427) [70]. In that population, significant improvements were observed in WPAI work impairment, the HAM-D17 work/activities item and the SDS work/studies item with desvenlafaxine 50 mg/d treatment versus placebo [90,91]. Significant improvement with desvenlafaxine treatment versus placebo was also observed in Q-LES-Q total score and 10 of 16 item scores [92]. Cognitive function was assessed in a subgroup of patients in the same study (n = 81) using the Cognitive Drug Research System [93]. Significant improvement after 12-week treatment with desvenlafaxine 50 mg/d versus placebo was observed on the memory composite score (Quality of Working Memory, p = 0.0008) and several tasks measuring memory speed and accuracy. Desvenlafaxine treatment was also associated with improvement in an executive functioning task (Trail Making Part B, p = 0.0398) [93]. Special populations/subgroups Desvenlafaxine efficacy for treating MDD has been demonstrated in several special populations and patient subgroups (Table 4). Perimenopausal and postmenopausal women with MDD achieved significant improvement in two placebocontrolled trials, a fixed-dose (50 mg/d) trial [71] and a flexible-dose (100 -- 200 mg/d) trial [94], although remission rates were significantly higher for the desvenlafaxine group (38%) versus placebo (22%; p = 0.008) in the higher dose trial, but not the lower dose trial (24 vs 17%). In subgroup analyses for each trial and for the trials pooled, desvenlafaxine efficacy was demonstrated for both perimenopausal and postmenopausal subgroups separately [61,84,85]; no effect of perimenopausal versus postmenopausal status was observed in the pooled analysis [85]. Longer-term efficacy data were collected in postmenopausal women initially enrolled in an 8-week, randomized, double-blind trial, comparator-controlled study of desvenlafaxine (100 -- 200 mg/d) versus escitalopram (10 -- 20 mg/d) [95,96]. Responders (‡ 50% reduction from baseline in HAM-D17 total score) to acute-phase treatment could receive an additional 6 months of double-blind treatment; nonresponders to either desvenlafaxine or escitalopram were eligible for 6-month open-label treatment with desvenlafaxine 100 -- 200 mg/d. No significant differences between desvenlafaxine and escitalopram were observed for maintenance of response in responders, and similar improvement in HAMD17 total scores was observed for patients assigned to acutephase desvenlafaxine (mean [SD] change, --18.82 [5.51]) and escitalopram treatment (--17.88 [4.96]) [95]. Desvenlafaxine efficacy was also demonstrated for several patient subgroups in the pooled desvenlafaxine registration trials or in pooled 50 mg/d trials. No differences in efficacy were observed by sex or by age group (18 -- 40 years; 41 -- 54; 55 -- 64; ‡ 65) in a subgroup analysis of the pooled registration 2.3.4

trials [97]. Desvenlafaxine 50 mg/d treatment significantly reduced symptoms of depression compared with placebo in both moderately depressed (18 < baseline HAM-D17 total score < 25) and severely depressed (HAM-D17 total score ‡ 25) subgroups of patients enrolled in six desvenlafaxine 50 mg/d trials [98]. Efficacy was also demonstrated in patients with moderate (12 £ SDS < 21) and severe (SDS ‡ 21) functional impairment in the same pooled trials [98], and in patients with anxious depression (HAM-D17 Anxiety-Somatization factor ‡ 7) in seven pooled 50 mg/day trials [99]. 2.4

Safety and tolerability Adverse event profile

2.4.1

The most common treatment-emergent adverse events (TEAEs) reported by desvenlafaxine-treated patients (‡ 5% and ‡ 2 times placebo rates) in the desvenlafaxine registration trials are listed by dose in Table 5 [100]. Desvenlafaxine tolerability is dose related; rates of the most common TEAEs and discontinuations due to adverse events (AEs) both increase with increasing desvenlafaxine dose [100]. Rates of discontinuation due to AEs were comparable for the 50 mg/d and placebo groups in a pooled analysis of fixed-dose registration trials for discontinuations due to AEs [100]. Nausea was the most common TEAE in the nine registration trials, reported by 22% of patients in the 50 mg/d group (placebo, 10%) [100] Incidence of nausea is highest in the first week of treatment, and returns to placebo levels thereafter [100]. Discontinuation symptoms Discontinuation from short-term or continuation desvenlafaxine treatment is associated with discontinuation-emergent symptoms [101,102], consistent with other antidepressant drugs [103]. Most common discontinuation-emergent symptoms include headache, nausea, and dizziness [101,102]. For the 50 mg/d desvenlafaxine dose, abrupt discontinuation is equivalent in tolerability to a 1-week taper to 25 mg/d [102]. 2.4.2

Sexual function In a secondary analysis of a 12-week, Phase IIIb trial in employed patients with MDD [70], overall sexual functioning, as measured by Arizona Sexual Experiences Scale (ASEX) [104] total score, was similar for patients taking desvenlafaxine 50 mg/d compared with patients taking placebo [105]. Effects of desvenlafaxine 50 and 100 mg/d doses on ASEX total score were also comparable to placebo in a recent 8-week, Phase IV study [75]. 2.4.3

Weight Changes in body weight during short-term and long-term desvenlafaxine treatment have been examined in two pooled analyses of short-term, double-blind, placebo-controlled studies (nine fixed- and flexible-dose studies [50 -- 400 mg/d]; eight fixed-dose studies [50 and 100 mg/d), and analyses of two placebo-controlled relapse prevention studies (9 months, 200 -- 400 mg/d; 11 months, 50 mg/d) [106,107]. Short-term 2.4.4


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Table 5. Most common treatment-emergent adverse events ($ 5% and at least two times greater with desvenlafaxine than with placebo) by dose.


Adverse event*

Nausea Dry mouth Hyperhidrosis Dizziness Insomnia Constipation Somnolence Decreased appetite Fatigue Erectile dysfunctionz Vomiting Tremor Mydriasis Anorgasmia

Desvenlafaxine Placebo n = 636

50 mg/d n = 317

100 mg/d n = 424

200 mg/d n = 307

400 mg/d n = 317

66 (10) 57 (9) 28 (4) 33 (5) 40 (6) 24 (4) 23 (4) 13 (2) 22 (4) 3 (1) 18 (3) 11 (2) 1 (< 1) 0

69 (22) 36 (11) 30 (10) 42 (13) 27 (9) 27 (9) 11 (4) 16 (5) 21 (7) 3 (3) 9 (3) 6 (2) 5 (2) 1 (< 1)

112 (26) 70 (17) 47 (11) 41 (10) 49 (12) 37 (9) 36 (9) 34 (8) 28 (7) 9 (6) 15 (4) 13 (3) 7 (2) 7 (2)

110 (36) 63 (21) 56 (18) 47 (15) 42 (14) 31 (10) 37 (12) 30 (10) 30 (10) 10 (8) 19 (6) 26 (9) 19 (6) 6 (2)

129 (41) 78 (25) 66 (21) 50 (16) 47 (15) 43 (14) 37 (12) 33 (10) 35 (11) 17 (11) 27 (9) 28 (9) 18 (6) 18 (6)

Adapted with permission from [100]. *Classification of adverse events is based on the Medical Dictionary for Regulatory Activities. z Percentage based on number of men.

desvenlafaxine treatment was associated with a small (< 1 kg) but significant short-term mean weight loss compared with placebo in both pooled analyses [106,107]. Mean weight change did not differ significantly between desvenlafaxine and placebo at the final evaluation in either long-term study [106,107].

have been approved [38,39]; treatment guidelines recommend dose increases for individual patients who do not respond to the initial antidepressant dose [6,7].

Suicidal ideation and behaviors A retrospective analysis of suicidal thoughts and behaviors was conducted based on a search of cases reports for each AE in the nine desvenlafaxine registration trials using methods primarily based on FDA data requests for suicide analyses [108,109]. No evidence of a signal for increased suicidal ideation and behaviors was detected in adult patients treated with desvenlafaxine 50 -- 400 mg/d [109]. Suicidal events are extremely rare; however, a true increased risk in adult patients treated with desvenlafaxine cannot be ruled out.

Desvenlafaxine has demonstrated efficacy for treating MDD at doses of 50 -- 400 mg/d [64-67,69-71]; no evidence of efficacy is reported at doses lower than 50 mg/d [69,72]. Continuation efficacy and safety, and increased time to relapse versus placebo has been demonstrated at the 50 mg/d dose [76-79,81]. Desvenlafaxine is effective for treating MDD in elderly patients [97], perimenopausal and postmenopausal women [71], patients with moderate or severe depression or functional impairment [98], and patients with anxious depression [99]. Desvenlafaxine reduced anxious symptoms and improved functional and QOL outcomes in pooled analyses [83,84,89,92]. Desvenlafaxine is generally safe and well tolerated [100]. The AE profile is consistent with other drugs in its class. Desvenlafaxine is not associated with clinically significant weight change during short- or longer-term treatment [106,107]. The effects of desvenlafaxine on sexual functioning are comparable to placebo [105]. No signal for increased suicidal thoughts or behaviors has been observed with desvenlafaxine treatment [109]. Desvenlafaxine has a low potential for DDIs mediated by the CYP system or P-gp [55-58,60,61,84].

2.4.5

QT interval A QTc study (n = 68) assessed the effect of desvenlafaxine doses 4 -- 12 times the recommended daily dose (200 and 600 mg/d). Desvenlafaxine did not significantly affect QTc (the two-sided 90% CI for desvenlafaxine compared with placebo excluded 10 ms), as measured by Fridericia’s correction and population-based correction, at 8 h postdose [data on file, Pfizer]. 2.4.6

Regulatory affairs Desvenlafaxine is approved for the treatment of MDD in over 30 countries, including the USA and Canada [38,39]. The US FDA recommended dose is 50 mg/d for adults with MDD [38]. Both the 50 and 100 mg/d dose formulations

3.

Conclusion

2.5

1456

4.

Expert opinion

SNRIs as a class are a first-line treatment options for MDD, as are SSRIs [6,7], with similar rates of remission, tolerability



Desvenlafaxine

and drug--drug interactions between the two classes [27,110]. It was initially expected that SNRIs would convey greater efficacy than SSRIs while retaining the side effect advantage over earlier antidepressants [111]; however, there is no consistent evidence that, as a class, they are superior to SSRIs [6,7]. Among the SNRIs, does desvenlafaxine offer any advantages or disadvantages? Advantages of desvenlafaxine include ease of dosing versus venlafaxine (50 or 100 mg [38]), a favorable safety and tolerability profile [100,112], no apparent sexual dysfunction over and above placebo [105], no clinically significant weight gain [106,107] and generally low rates of discontinuation symptoms for the 50 mg dose [102]. In addition, a low risk of drug-drug interactions has been demonstrated with desvenlafaxine. Desvenlafaxine has a simple biotransformation pathway, largely independent of the Phase I CYP enzyme system [44], whereas venlafaxine and duloxetine are metabolized primarily via CYP enzymes [46,113]. Reduced exposure to the active metabolite in CYP 2D6 poor metabolizers [51,52] can result in poorer efficacy for venlafaxine (vs extensive metabolizers) [53], but desvenlafaxine exposure is unaffected by CYP 2D6 metabolizer status [51], suggesting that CYP 2D6 poor metabolizers may be considered for treatment with desvenlafaxine [114]. There have been no direct (head-to-head) comparative studies evaluating the efficacy, safety and/or tolerability of desvenlafaxine to venlafaxine. However, an indirect meta-analysis based on comparisons with placebo indicated that the efficacy of desvenlafaxine (50 -200 mg/d) for treating MDD is not inferior to that of venlafaxine (75 -- 225 mg/d) [112]. Pricing and reimbursement issues continue to be a major disadvantage for desvenlafaxine versus venlafaxine or duloxetine, although a large, retrospective database claims analysis found that desvenlafaxine treatment was associated with significantly lower MDD-related and overall healthcare costs compared with both venlafaxine and duloxetine [115]. Additional disadvantages include few direct comparative studies evaluating the efficacy, safety and/or tolerability of desvenlafaxine to other antidepressants, and a paucity of data regarding the efficacy of desvenlafaxine (as well as most other antidepressants) in the treatment of comorbid conditions (e.g., generalized anxiety disorder, social anxiety disorder). The early development of desvenlafaxine sought to determine the utility of this agent for disparate indications including pain (e.g., diabetic painful neuropathy, fibromyalgia) and vasomotor symptoms (VMS). Efficacy for pain was observed at higher desvenlafaxine doses [200 mg]) [116], and desvenlafaxine efficacy for treating moderate to severe VMS was demonstrated in four out of five Phase III clinical trials, as measured by reduced number and severity of hot flushes [117-121]. In fact, desvenlafaxine has been approved for a VMS indication in several countries but is not approved for VMS in the USA or Canada. The efficacy of desvenlafaxine has been studied both in general MDD populations and in several specific subpopulations, and it is in those subpopulations that desvenlafaxine may likely have the greatest impact on current treatment strategies. Clinical trials have been conducted in perimenopausal and postmenopausal women with depression [71,94] and in employed patients

with MDD, who had to be working at least 20 h per week to be enrolled in the trial [70]. No previous large randomized controlled trials of antidepressants have been conducted in these subpopulations. Desvenlafaxine thus may be considered the first choice among antidepressants for perimenopausal and postmenopausal women and employed patients. Although other antidepressants may also be effective, efficacy cannot be assumed for populations that have not specifically been studied. Subgroup analyses also have been conducted on desvenlafaxine clinical trial data and have demonstrated efficacy in perimenopausal women only and postmenopausal women only [85], and in patients grouped by age and sex [97], by baseline severity of depression [98], by baseline functional impairment [98] and by anxious versus nonanxious depression [99]. Some additional studies of desvenlafaxine could provide useful information. Specifically, a study of the efficacy of dose increases in nonresponders/nonremitters at the 50 mg dose would be useful in guiding clinicians. Previous studies have assessed dose effects based on group mean scores only and have not addressed this issue on the individual patient level [74]. Other needed treatment studies are large, placebo-controlled, maintenance therapy trials (duration > 12 months), additional head-to-head comparisons with other SNRIs, and switching studies from SSRIs or venlafaxine to desvenlafaxine. Furthermore, like most other antidepressants, desvenlafaxine has not been adequately studied in individuals who have been insufficiently responsive to a separate first-line antidepressant agent. In addition to these, it would be useful to examine the contribution of NE transporter inhibition to desvenlafaxine efficacy and also to compare the tolerability of desvenlafaxine versus venlafaxine in CYP 2D6 poor metabolizers. Desvenlafaxine has been studied in numerous short-term and continuation efficacy and safety trials, mainly in the general MDD population, and these proposed additional studies will provide data to further elucidate its place among other antidepressant drugs on the market. Regarding future expectations, desvenlafaxine has advantages over some other antidepressants, including simplicity of dosing, tolerability, low risk of drug--drug interactions and demonstrated efficacy in subpopulations (perimenopausal and postmenopausal women, employed patients). These advantages have not yet led to a substantial increase in prescriptions since launch. It is likely that factors unrelated to efficacy and tolerability may have resulted in a suppressed number of prescriptions, for example, access and reimbursement (cost to the patient). Overall, desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile. It has demonstrated efficacy in the general MDD population and in important patient subgroups. The areas in which it is differentiated from the other drugs in the SNRI class -including established efficacy in those patient subgroups and its simple biotransformation pathway -- suggest particular patient populations in which it may have the most clinical benefit.


1457



Declaration of interest S Kornstein has received research grants from Forest, Roche, Allergan, BMS and has consulted for Takeda, Pfizer, Shire, Naurex, Lilly, Forest, Lundbeck. RS McIntyre has been on advisory boards for AstraZeneca, BMS, France Foundation, GlaxoSmithKline, Janssen-Ortho, Eli Lilly, Organon, Lundbeck, Pfizer, Shire, Merck; speakers bureaus for Janssen-Ortho, AstraZeneca, Eli Lilly, Lundbeck, Merck, Pfizer; CME activities for AstraZeneca, BMS, France Foundation, I3CME, Physicians’ Postgraduate Press, CME Outfitters, Optum Health, Merck, Eli Lilly, Pfizer; and has received research grants from Eli Lilly, Janssen-Ortho, Shire, Astra-Zeneca, Pfizer, Lundbeck. M Thase has been an advisor/consultant for Alkermes, AstraZeneca, BMS, Cerecor, Eli Lilly, Dey Pharma, Forest, Gerson Lehman, GlaxoSmithKline (ended 2008), Guidepoint Global, Lundbeck, MedAvante, Merck, Neuronetics, Novartis (ended 2008), Otsuka, Ortho-McNeil, Pamlab, Pfizer, PGx, Shire, Sunovion, Supernus, Takeda, Transcept Pharmaceuticals; has received grant support from Agency for Healthcare Research and Quality, Alkermes (ended 2013), Eli Lilly (ended 2012), Forest, NIMH, Otsuka, PharmaNeuroboost (ended 2013), Roche (ended 2013); and has received equity holdings Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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from MedAvante; royalties from American Psychiatric Foundation, Guilford Publications, Herald House, WW Norton & Company; spouse employed by Peloton Advantage, which does business with Pfizer. M Boucher is an employee of Pfizer. Manuscript development was funded by Pfizer. Editorial/ medical writing support was provided by Kathleen Dorries, PhD, of Peloton Advantage, LLC, and was funded by Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. In September 2011, Pfizer received a Complete Response Letter from the US Food and Drug Administration on its application for approval to market desvenlafaxine for the treatment of moderate to severe VMS associated with menopause. The Complete Response Letter states that the data included in the application are not sufficient to establish an acceptable risk/benefit profile for the treatment of VMS in the general population of postmenopausal women, and therefore desvenlafaxine is not approved for the treatment of VMS in the United States at this time. This decision does not impact the approval of desvenlafaxine for the treatment of MDD in adults.

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Affiliation

Susan G Kornstein†1 MD, Roger S McIntyre2 MD FRCPC, Michael E Thase3 MD & Matthieu Boucher4 PhD † Author for correspondence 1 Department of Psychiatry and Institute for Women’s Health, Virginia Commonwealth University, PO Box 980319, Richmond, VA 23298-0319, USA Tel: +1 804 827 1200; Fax: +1 804 827 0957; E-mail: [email protected] 2 University of Toronto, Toronto, Ontario, Canada 3 University of Pennsylvania, Philadelphia, PA, USA 4 Pfizer Canada Inc, Kirkland, Quebec, Canada


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A pooled analysis of the efficacy of desvenlafaxine for the treatment of major depressive disorder in perimenopausal and postmenopausal women.

Effects of desvenlafaxine on blood pressure in patients treated for major depressive disorder: a pooled analysis.

Levomilnacipran for the treatment of major depressive disorder: a review.

[Botulinum toxin for the treatment of major depressive disorder].

Vortioxetine for the treatment of major depressive disorder.

Safety and tolerability of desvenlafaxine in children and adolescents with major depressive disorder.

Predictors of functional improvement in employed adults with major depressive disorder treated with desvenlafaxine.

Updated CANMAT Guidelines for Treatment of Major Depressive Disorder.

Hyperthermia for Major Depressive Disorder?

Psychosocial Treatment Options for Major Depressive Disorder in Older Adults.

Neuroimaging-based biomarkers for treatment selection in major depressive disorder.

The bipolar diathesis of treatment-resistant major depressive disorder.

Lithium in the treatment of major depressive disorder.

d as a predictor of treatment success in patients with major depressive disorder.

Adjunctive treatment with quetiapine for major depressive disorder: are the benefits of treatment worth the risks?

Major depressive disorder.

Risks for suicidality in major depressive disorder.

Neurobiology of major depressive disorder.

The mistreatment of major depressive disorder.

d vs placebo in employed adults with major depressive disorder.

[Cognition - the core of major depressive disorder].

Rare copy number variation in treatment-resistant major depressive disorder.

Pramipexole augmentation in treatment-resistant major depressive disorder.

Psychological treatment for depressive disorder.