Osmotic-Release Oral System Methylphenidate Augmentation of Antidepressant Monotherapy in Major Depressive Disorder: Results of a Double-Blind, Randomized, Placebo-Controlled Trial
Abstract
Objective To evaluate the efficacy, safety, and tolerability of adjunctive osmotic-release oral system (OROS) methylphenidate in outpatients with major depressive disorder (MDD) receiving a stable oral antidepressant regimen. Method This multicenter, double-blind, randomized, placebo-controlled, parallel-group, 5-week trial enrolled 145 subjects who met DSM-IV-TR criteria for MDD and who had failed 1 to 3 previous antidepressant monotherapies (including current antidepressant) of adequate dose and duration. Augmentation therapy was initiated with 18 mg of OROS methylphenidate and increased to a maximum dose of 54 mg of OROS methylphenidate until an optimal dose was achieved. Efficacy scales included the Montgomery-Asberg Depression Rating Scale (MADRS), 7 atypical items from the 31-item Hamilton Rating Scale for Depression, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the CGI-Improvement scale (CGI-I), the Sex Effects scale, the Multidimensional Assessment of Fatigue (MAF) scale, and the Apathy Evaluation Scale (AES). Subjects were recruited at 17 community and academic centers across Canada. The study was conducted from June 8, 2005, to April 18, 2006. Results There was no statistically significant difference between the groups at endpoint on the MADRS. OROS methylphenidate was superior to placebo in improving apathy and fatigue as measured by the AES and the MAF. Statistically significant differences using mixed-model analysis were observed on the AES…
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Methylphenidate has been reported to be efficacious in reducing apathy in individuals with Alzheimer's disease and apathy and fatigue in individuals with MDD.
“In support of the latter hypothesis, methylphenidate has been reported to be efficacious in reducing apathy in individuals with Alzheimer's disease (Rosenberg et al., 2013) and apathy and fatigue in individuals with MDD (Ravindran et al., 2008).”
From Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies (2016) · cites this paper as Ravindran et al., 2008
These findings are generally consistent with published findings for psychostimulant and modafinil augmentation studies for MDD and with the conclusions of published meta-analyses.
“but they are generally consistent with published findings for psychostimulant (Patkar et al., 2006;Postolache et al., 1999;Ravindran et al., 2008) and modafinil augmentation studies for MDD (DeBattista et al., 2003;Dunlop et al., 2007;Fava et al., 2007) and with the conclusions of published meta-analyses (Candy et al., 2008;Fleurence et al., 2009).”
From Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies (2016) · cites this paper as Ravindran et al., 2008
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“A few studies have addressed residual symptoms, such as fatigue or sexual dysfunction.(134,135) However, there is no consistent evidence to support specific adjunctive agents to target specific residual symptoms or side effects.”
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“Two randomised placebo controlled trials of augmentation with the stimulant methylphenidate have also failed to demonstrate efficacy (Patkar et al., 2006; Ravindran et al., 2008).”
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“Two RCTs of augmentation with the CNS stimulant, methylphenidate, failed to detect differences in outcomes from placebo (Patkar et al., 2006; Ravindran et al., 2008) and a Cochrane systematic review found equivocal results for psychostimulants as augmentation to antidepressants (Candy et al.”
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“Combination with psychostimulants Several negative studies indicate that methylphenidate is not reliably efficacious as an adjunct to conventional antidepressant therapy in adults with MDD (Ravindran et al., 2008; Patkar et al., 2006).”
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“(2008), also failed to show an antidepressant effect of stimulants as add-on (Beck et al., 2010; Dunlop et al., 2007; Ravindran et al., 2008), with the exception of one small short-term trial with modafinil add-on (Abolfazli et al.”
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“Another placebo-controlled trial of OROS -methylphenidate in 2008 similarly failed to find a significant difference in primary depression outcomes in a sample of 145 subjects with a history of one to three failed antidepressant treatments, although the stimulant group again had a numerically superior outcome.([58])”
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BackgroundThe Role of Dopamine in Symptoms and Treatment of Apathy in Alzheimer's Disease
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“Ravindran 2008 [138] Double-blind randomized controlled trial 145 patients with major depression taking an SSRI or Dual action agent antidepressant Methylphenidate OROS (18–54 mg/day) or placebo Improvement in symptoms of apathy (based on AES) in treatment group compared to placebo (P = 0.”
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“While this had the advantage of permitting direct quantitative comparisons across studies, it also limited the scope of the review by excluding additional studies on fatigue that did not meet these criteria, including studies of bupropion [62, 63], venlafaxine [64], levomilnacipran [65, 66] and osmotic release oral sy…”
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“However, in randomized trials in depression, augmentation with methylphenidate has not demonstrated a statistical benefit over standard therapy alone (Patkar et al., 2006; Michelson et al., 2007; Ravindran et al., 2008; Pary et al., 2015).”
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“Ravindran et al reported that patients with majör depressive disorder who did not respond a variety of antidepressant agents including SSRIs did not also respond toosmotic controlled-release oral delivery systemmethylphenidateof 18 to54mgper day,without anyconsiderable change in the Montgomery–Asberg Depression Rating…”
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“However, OROS methylphenidate was more effective than placebo in improving apathy and fatigue (Ravindran et al., 2008).”
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- Authors
- Ravindran, A. V., Kennedy, S. H., O'Donovan, M. C., Fallu, A., Camacho, F., & Binder, C. E.
- Affiliations
- University of Toronto (CA)
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2008-01-15
- Volume
- 69
- Issue
- 1
- Pages
- 87-94
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W1987459299
- Cited by
- 119
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 8 · 2016: 6 · 2015: 14 · 2014: 13 · 2013: 13 · 2012: 7
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- osmotic-release oral system, OROS methylphenidate, major depressive disorder, antidepressant-resistant depression, apathy, fatigue, tolerability, adverse effects
- MeSH terms
- Adult, Central Nervous System Stimulants, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Drug Synergism, Drug Therapy, Combination, Female, Humans, Male, Methylphenidate, Middle Aged, Severity of Illness Index, Diagnostic and Statistical Manual of Mental Disorders
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