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
Open accessAbstract
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.
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Two large phase 3 studies and a phase 2 study of lisdexamfetamine dimesylate augmentation in adults with MDD and inadequate response to antidepressant therapy failed to meet their primary efficacy endpoint versus placebo.
“In addition, 2 large phase 3 studies and a phase 2 study of lisdexamfetamine dimesylate augmentation in adults with MDD and inadequate response to antidepressant therapy failed to meet their primary efficacy endpoint versus placebo (234, 235).”
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- Authors
- Richards, C., Iosifescu, D. V., Mago, R., Sarkis, E., Reynolds, J., Geibel, B., & Dauphin, M.
- Affiliations
- Formerly of Shire, Lexington, USA
- New York University (US)
- Private Practice, Philadelphia, USA
- Sarkis Family Psychiatry, Gainesville, USA
- Corresponding author
- Reynolds, James
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2017-08-31
- Volume
- 31
- Issue
- 9
- Pages
- 1190-1203
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- PMC
- PMC5606302
- OpenAlex
- W2751865667
- Cited by
- 14
- References
- 34
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1 · 2018: 4
- FWCI
- 0.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Psychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- lisdexamfetamine dimesylate, major depressive disorder, antidepressant augmentation, treatment-resistant depression, dose-response relationship, escitalopram, venlafaxine extended release, vital signs, blood pressure, heart rate, Montgomery-Asberg Depression Rating Scale, adverse events, stimulants, children and adolescents
- MeSH terms
- Venlafaxine Hydrochloride, Lisdexamfetamine Dimesylate, Adult, Antidepressive Agents, Blood Pressure, Major Depressive Disorder, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Citalopram
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