A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy

Abstract

Background: This randomized, double-blind, placebo-controlled study evaluated dose-response relationships of lisdexamfetamine dimesylate when used as augmentation for major depressive disorder in individuals exhibiting inadequate responses to antidepressant monotherapy.

Methods: Eligible adults (18-65 years) were assigned to antidepressant monotherapy (escitalopram or venlafaxine extended-release) plus lisdexamfetamine dimesylate-matching placebo during an eight-week single-blind lead-in phase. Participants meeting randomization criteria were randomized (1:1:1:1:1) to eight weeks of lisdexamfetamine dimesylate (10, 30, 50, or 70 mg) or placebo while maintaining antidepressant therapy. Dose-responses for changes from augmentation baseline to week 16/early termination for Montgomery-Åsberg Depression Rating Scale total score (primary efficacy endpoint) and vital signs (systolic and diastolic blood pressure and pulse) were assessed using multiple comparisons procedures with modeling.

Results: For Montgomery-Åsberg Depression Rating Scale total score change, no significant dose-responses were observed for any candidate dose-response curve (all p>0.10). In the dose-response evaluable population, least squares mean (90% confidence interval) treatment differences versus placebo for Montgomery-Åsberg Depression Rating Scale total score change at week 16 were -1.4 (-3.9, 1.2), 0.1 (-2.5, 2.7), -0.7 (-3.4, 2.0), and -0.9 (-3.5, 1.6) with 10, 30, 50, and 70 mg lisdexamfetamine dimesylate, respectively. For all vital sign parameters, lisdexamfetamine dimesylate exhibited significant dose-responses for all candidate dose-response curves (all p<0.10), with increases observed as lisdexamfetamine dimesylate dose increased; a linear relationship provided the best fit. Mean±standard deviation changes from augmentation baseline for systolic and diastolic blood pressure and pulse at week 16/early termination were -0.7±9.90 and -0.3±7.24 mm Hg and 0.2±10.57 bpm with placebo and were 1.9±9.47 and 0.8±7.40 mm Hg and 3.6±9.74 bpm with lisdexamfetamine dimesylate (all doses combined). The safety and tolerability profile of lisdexamfetamine dimesylate was consistent with previous studies.

Conclusions: Lisdexamfetamine dimesylate augmentation did not provide benefit over placebo in adults with inadequate responses to antidepressant monotherapy based on the assessed efficacy measures.

Trial registration: ClinicalTrials.gov NCT01435759.

Keywords: Major depressive disorder; augmentation; dose-response; lisdexamfetamine; multiple comparisons procedure with modeling.

Conflict of interest statement

Declaration of conflicting interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C Richards, J Reynolds, M Dauphin, and B Geibel are former employees of Shire and hold stock and/or stock options in Shire. D Iosifescu, in the past three years, has consulted for Avanir, Axsome, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, and Sunovion and received research support through the Icahn School of Medicine at Mount Sinai from Alkermes, AstraZeneca, Brainsway, Euthymics, Neosync, Roche, and Shire. R Mago, in the past three years, has received research grants through Thomas Jefferson University from Alkermes, Forest Research Institute, Genomind, Shire Development, and has done consultations for Forest Laboratories, GuidePoint Global, Nestle Health Science, Otsuka America Pharmaceuticals, and Sunovion, and has received payment through Thomas Jefferson University from Shire US for live training. E Sarkis, in the past three years, has conducted clinical trials with Alkermes, Allergan, AstraZeneca, Auspex, Daiichi-Sankyo, Eli-Lilly, Forest, GlaxoSmithKline, Lundbeck, Neurim, Otsuka, Pfizer, Purdue, Shire, Sunovion, and Tonix.

Figures

Figure 1.

Study timeline and dose adjustment schedule for (a) randomized and (b) nonrandomized participants. LDX: lisdexamfetamine dimesylate; V: visit; Wk: week.

Figure 2.

Prespecified candidate dose-response curves used for multiple comparisons procedure with modeling (MCP-Mod) assessment of Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

Figure 3.

Participant disposition. aSustained elevations in average sitting systolic blood pressure (SBP) (increases of ⩾10 mm Hg from antidepressant lead-in baseline and an average value ⩾140 mm Hg on two consecutive visits), average sitting diastolic blood pressure (DBP) (increases of ⩾10 mm Hg from antidepressant lead-in baseline and an average value ⩾90 mm Hg on two consecutive visits), or average pulse (increase of ⩾20 bpm from antidepressant lead-in baseline and an average value ⩾100 bpm on two consecutive visits). bParticipants whose depressive symptoms improved but did not meet the randomization criteria; allocated to single-blind placebo in conjunction with the antidepressant therapy assigned during the antidepressant lead-in phase. BP: blood pressure; DRES: dose-response evaluable set; LDX: lisdexamfetamine dimesylate; VSES: vital signs evaluable set.

Figure 4.

Dose-response relationship between the lisdexamfetamine dimesylate (LDX) dose test (10–70 mg/d) for (a) systolic blood pressure, (b) diastolic blood pressure, and (c) pulse rate.