Analysis of the Effect of Desvenlafaxine on Anxiety Symptoms Associated vs ith Major Depressive Disorder: Pooled Data from 9 Short-Term, Double-blind
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Original Research Analysis of the Effect of Desvenlafaxine on Anxiety Symptoms Associated vs^ith Major Depressive Disorder: Pooled Data from 9 Short-Term, Double-blind, Placebo-Controlled Trials Karen A. Tourian, MD, Qin Jiang, MS, and Philip T. Ninan, MD ABSTRACT FOCUS POINTS Background: This analysis evaluated the Symptoms of anxiety are commonly associ- effects of the serotonin-norepinephrine reup- ated with major depressive disorder (MDD). take inhibitor, desvenlafaxine (administered as Desvenlafaxine is a serotonin-norepineph- rine reuptake inhibitor approved for the desvenlafaxine succinate), on anxiety symptoms treatment of MDD. associated with depression. This post-hoc analysis evaluated the efficacy of Methods: Data were pooled from 9 random- desvenlafaxine (50-400 mg/day) compared with placebo in the treatment of anxiety symp- ized, placebo-controlled, double-blind, 8 week toms associated with MDD, using pooled individ- studies of desvenlafaxine (50-400 mg/day, fixed ual patient data from 9 short-term, randomized, or flexible dose) in patients with major depres- double-blind, placebo-controlled clinical trials. Desvenlafaxine treatment was associated with sive disorder (MDD), without a primary anxiety significantly greater improvement on measures diagnosis. Changes from baseline in scores on of anxiety compared with placebo in outpatients with a primory diognosis of MDD. the anxiety/somatization factor of the 17-item Hamilton Rating Scale for Depression (HAM-D17) and on the Covi Anxiety Scale at the final eval- cebo, n=1,108]), desvenlafaxine was associated uation (last observation carried forward) were with significantly greater reductions compared compared between desvenlafaxine and placebo with placebo in scores on the HAM-Diy anxi- groups using analysis of covariance. ety/somatization factor (-3.41 vs -2.92, P
Original Research differences were observed for all dose groups it is expected that treatment with des- on the HAM-D17 anxiety/somatization factor venlafaxine will result in significant improvement of anxiety symptoms associated with MDD. The (Ps.OII), and for the 50, 100, and 200 mg/day objective of this post hoc analysis of pooled short- dose groups on the Covi Anxiety Scale {all term studies was to compare the efficacy of des- Ps.O15 vs placebo). venlafaxine and placebo in reducing symptoms of anxiety in outpatients with a primary diagnosis Conclusions: Desvenlafaxine was associ- of MDD. The effects of baseline anxiety on overall ated with significantly greater improvement in treatment outcomes and the relationship between anxiety symptoms connpared with placebo in improvement in anxiety symptoms and remission were not evaluated in this analysis. patients with MDD. CNS Spectr. 2010;15(3):187-193 METHODS INTRODUCTION Study Design Although major depressive disorder (MDD) This secondary analysis evaluated the effect is characterized primarily by depressed mood of desvenlafaxine on anxiety symptoms in adult and a loss of interest or pleasure in daily activi- outpatients with MDD using pooled data from 9 ties, many cases also are accompanied by some short-term, randomized, double-blind, placebo- symptoms of anxiety\- -50% of cases in the controlled, multicenter studies of desvenlafaxine. Sequenced Treatment Alternatives to Relieve These phase II and III clinical trials comprise the Depression (STAR*D) study met criteria for anx- portfolio of the US Food and Drug Administration ious depression (defined as a score of >7 on registration studies for the treatment of MDD (Table the anxiety/somatization factor of the Hamilton 12125,29) ^11 studies were approved by an inde- Rating Scale for Depression [HAM-D]).^^ The pendent ethics committee or institutional review coexistence of anxiety symptoms, especially board, were conducted in accordance with the eth- severe anxiety, increases the severity of depres- ical principles in the Declaration of Helsinki, and sive illness and worsens functional impairment. were consistent with Principles of Good Clinical In some reports,^^ but not all,^' anxious depres- Practice and applicable regulatory requirements. sion decreased the likelihood of response or All studies included in this pooled analysis had remission, and/or increased the time to achieve similar study designs and patient samples. response or remission with treatment for MDD, which underscores the importance of treating both depression and MDD-associated anxiety. Study Patients To be eligible for inclusion in any of the 9 tri- A significant overlap exists in pathophysiologic als, outpatients (218 years of age) were required components of depression and anxiety, and treat- to have a primary diagnosis of nonpsychotic ment of both.^ Antidepressants from a variety of MDD based on the Diagnostic and Statistical classes, particularly selective serotonin reuptake Manual of Mental Disorders, Fourth Edition^° inhibitors and serotonin-norepinephrine reuptake criteria, with depressive symptoms that had inhibitors (SNRIs), are effective in treating anxiety been present for at least 1 month. Patients had disorders^ '^ in addition to treating symptoms of to have a current, moderate to severe depressive anxiety associated with MDD.* '^'^ episode at both screening and baseline. Criteria Desvenlafaxine (administered as desvenla- for severity of depression included a 17-item faxine succinate), the active metabolite of venla- HAM-D^^ total score 220 (4 studies) or a22 {2 faxine, is an SNRI approved in the United States studies) or a Montgomery Asberg Depression for the treatment of MDD.'^'^° Several phase III, Rating Scale^^ score 2r24 {1 study); HAM-Di7 item randomized, placebo-controlled, double-blind 1 (depressed mood) score z2; and Clinical Global studies have established the efficacy, safety, and Impressions-Severity scale^^ total score &4; in 8 tolerability of desvenlafaxine in treating MDD in of the 9 studies, patients were required to have a adult outpatients.^^ ^^ Covi Anxiety Scaie^"* score ^3 on any single item, Based on the established efficacy of other and a Covi Anxiety Scale total score ^9 and less SNRIs in the treatment of anxiety symptoms than the Raskin Depression Scate^^ total score. associated with MDD or primary anxiety disor- Patients were excluded from eligibility for any CNS Spectr 15:3 188 March 2 0 1 0
Original Research of the 9 trials if they had a current W\2 months items 10 [anxiety/psychic], 11 [anxiety/somaticl, before baseline) primary diagnosis of an anxiety 12 [somatic/gastrointestinal], 13 [somatic/gen- disorder (eg, generalized anxiety disorder, social eral], 15 [hypochondriasis], and 17 [insight]) score, anxiety disorder, or panic disorder). All patients the HAM-D17 anxiety-psychic item score, and provided written, informed consent. the Covi Anxiety Scale total score. The HAMD-ij was administered in all 9 studies at baseline and Treatments weeks 1, 2, 3, 4, 6, and 8. The Covi Anxiety Scale Eligible patients were randomly assigned to was administered in 8 of 9 studies at baseline and receive desvenlafaxine at doses ranging from weeks 2, 4, and 8; this scale was not administered 50-400 mg/day {n=1,805) or placebo (n=1,108). in the phase 2 study {Table 1). Four studies used a flexible-dose regimen of des- venlafaxine 100-400 mg/day (100-200 mg/day Statistical Analysis [1 study]; 200-400 mg/day [3 studies]}; 5 studies Data from the intent to treat {ITT) population used a fixed dose desvenlafaxine regimen (50 were analyzed. The ITT population included mg/day, 2 studies; 100 mg/day, 3 studies; 200 mg/ patients who had a baseline evaluation, al dose day, 3 studies; and 400 mg/day, 3 studies) {Table of study medication, and &1 HAM-D17 evalua- 1). Data from patients assigned to receive venla- tion after receiving dose 1 of study medication. faxine extended release 75-226 mg/day {in 2 of Changes from baseline in HAM-D^y anxiety/ the studies) are not described in this report. The somatization factor, HAM-D17 anxiety-psychic duration of treatment in each study was 8 weeks. item, and Covi Anxiety Scale scores were ana- lyzed using an analysis of covariance (ANCOVA) Outcomes model using baseline scores as the covariate, The efficacy measures for this analysis were adjusted by protocol to test the treatment effect. the HAM-Di7 anxiety/somatizationfactor^^ (sum of The primary time point was the final evaluation. TABLE 1 . Studies Included in Meta-Analysis of Desvenlafaxine in Treating MDD-Related Symptoms of Anxiety: ITT Population Desvenlafaxine Study Desiqn Dose (ma/day) Desvenlafaxine (n) Placebo (n) Total (NI 223'' Phasen,fixed dose 200 63 78 213 400 72 306" Phase III, fixed-dose 100 114 118 461 200 116 400 113 308^' Phase III, fixed-dose 200 121 124 369 400 ^ ^ H^ 124 332'^ Phase III,fixed-dose 50 150 150 447 100 147 333" Phase 111, fixed-dose 50 164 161 483 100 ^ 304" Phase III, flexible-dose 100-200 120 114 234 320* Phase III, flexible-dose 200-400 117 118 235 309^^ Phase III, flexible-dose 200^00 116 120 236 317« Phase III, flexible-dose 200^00 110 125 235 Total 1,805 1.108 2,913 ' Data on die, Wyelh Research, Collegeville, PA. MDO-major depressive disorder; ITT=intent to treat Toiiriaii KA, Jiang Q, Ninan PT. CNS Spectr. Vo\ 15, No 3. 2010 CNS Spectr 15:3 189 March 2010
Original Research using last observation carried forward (LOCF) Efficacy methods for missing data; data from each visit Among all studies and for individual des- (LOCF) were also analyzed. In addition to the venlafaxine dose groups, there was significant analysis of the overall data set, an analysis of improvement from baseline HAM-Di7 anxiety/ data from the subset of fixed-dose studies was somatization factor score at the final evaluation conducted to evaluate the efficacy of each dose compared with placebo (Ps.011; Figure 1). In of desvenlafaxine. Cohen's d effect sizes were the overall data set, significant improvement calculated based on the mean change from base- was apparent by week 3 (P
Original Research chic item were -0.27 for the overall data set and group (P=.OO9) and by week 8 for the 50 mg/day were -0.29, -0.34, -0.35, and -0.35 for the 50, 100, dose group (P
Original Research mately -3.0 to -4.0 and the magnitude of the augmenting an ineffective or intolerable treat- difference between drug and placebo (approxi- ment.^ This finding demonstrates that It is critical mately -0.5) on the HAM-Di7 anxiety/somatiza- to recognize anxious depression and to choose tion factor reported here, are similar to or greater treatment options accordingly. An analysis of than those observed after 6-8 weeks of treat- pooled data from clinical trials of venlafaxine in ment with other SNRIs, such as venlafaxine.^^ MDD suggests that significant improvement in Although this analysis demonstrated statistically anxiety symptoms may be achieved as early as significant differences between desvenlafaxine the first week of treatment and early resolution of and placebo, the results should be considered anxiety symptoms may be a predictor of remis- in light of the large sample size used here, and sion of MDD.'' In this analysis, some dose groups as such, the clinical significance of these differ- showed a reduction of anxiety symptoms by ences may be limited. The effect sizes across all week 2 after initiation of treatment with desven- measures and all desvenlafaxine dose groups of lafaxine (Figures 2 and 5); however, the relation- -0.14 to -0.35 are in the range generally consid- ship between improvement in anxiety symptoms ered small to moderate. The recommended 50 and remission was not evaluated. mg/day dose of desvenlafaxine was associated There are limitations to pooled analyses, one with an effect size of -0.29 on each measure; this of which is related to study selection.^^ Often effect size is similar in magnitude to the effect only positive trial results are published^'; the size of -0.31 for the 50 mg/day dose group deter- exclusion of unpublished data generally results mined in a previous analysis of overall efficacy in the exclusion of data from negative trials, based on the primary outcome measure (change thereby skewing the results of the analysis. in HAM'Di7 total score).^^ However, this analysis included published and The utility of desvenlafaxine in treating anxiety unpublished data from all 9 short-term, pla- symptoms that accompany MDD is a particularly cebo-controiled, registration studies of desven- pertinent measure in light of recent data from iafaxine in patients with MDD; both positive and the STAR*D study showing that patients with anxious depression do not achieve remission as quickly or as frequently compared with patients FIGURE 5. with non-anxious depression and are likely to Adjusted mean Covi Anxiety Scale have poorer outcomes after switching from or scores, adjusted means by visit (LOCF) ^ P l a c e b o (n=1,026l - Oesvenlafaxme 50 mg (n=3I2| FIGURE 4 . •-Desvenlafaxine 100m9(n=4n) - Desvenlafaxine 200 mg in:232) Adjusted mean (SE) change fram •— Desvenlataxme 400 mg |n=234) - Dflsvenlafaxme Pooled in-1,6471 baseline in the Covi Anxiety Scale scores at the final evaluation (LOCF) P values reflect individual desvenlafaxine dose comparisons with Iheir respective placebo groups, n=number o) patients in each treatment group affinal evaluation. Week 2,*P=.O33 for 200 mg/day; Week 4, tPs.D15 for 200 and 100 mg/dav, Placebo • Desvenlafsxine ÎP
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