Lisdexamfetamine for Depression

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Major depressive disorder (MDD) is one of the most commonly diagnosed mental illness in the United States. The lifetime prevalence of MDD in US adults is 20.6%, and the prevalence of depression in adults and adolescent has been increasing over the last 25 years [1]. MDD is highly recurrent and is associated with functional impairment, psychiatric and substance use disorders, mortality, poor health and disability-years, and economic burden [1]. Current first-line treatment options for MDD includes second-generation antidepressants such as selective serotonin antidepressants or selective serotonin-norepinephrine reuptake inhibitors [2].

Many patients fail to respond to current MDD monotherapies or augmentation therapies adequately. Furthermore, current treatment does not always result in remission. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) showed low remission rates with monotherapy citalopram and adding augmentation therapy [3]. Some of the current augmentation options for depression are associated with different tolerability and safety concerns. Up to 63% of patients on second-generation antidepressants experience adverse side effects, and about 7% to 15% of patients discontinue the treatment because of it [2].

Historically, there has been an interest in using stimulants for MDD, but very little research is currently available on its effectiveness for MDD. This article will review and evaluate available research on the use of Lisdexamfetamine Dimensaylate (LDX) as augmentation therapy for MDD.

LDX efficacy and safety

LDX is a pharmacologically inactive form of d-amphetamine, a stimulant, currently used for ADHD in adolescents, and adults [4]. It is one of the augmentation therapy options for MDD [5, 6]. A study done by Madhoo et al. evaluated the role of LDX augmentation therapy in executive dysfunction in partially or fully remitted MDD [6]. The study was a random, placebo-controlled study which enrolled 143 adults (18-55 years), with mild MDD and executive dysfunction over 9-week double-blind LDX augmentation or placebo, followed by two weeks of single-blind placebo trial. The study participants were stable on antidepressants monotherapy for more than eight weeks before undergoing the trial. The results indicated that patients with mild MDD, LDX augmentation therapy significantly improved executive dysfunction and depressive symptoms [6]. The 52-week open-label extension study conducted at 207 sites in 17 countries between 2012 to 2014 evaluated tolerability and safety of LDX in adults with MDD [5].

Furthermore, in phase-II of short-term efficacy study, LDX augmentation of antidepressant monotherapy for MDD produced more reductions in Montgomery-Asberg Depression Rating Scale (MADRS) than the placebo. However, in phase-III short-term efficacy study, differences between LDX and placebo was not statistically significant for change in MADRS score [5]. Furthermore, phase-II dose-finding study of LDX (10-70mg), augmentation therapy did not find a significant change in dose response for MADRS [5]. LDX was not superior to placebo in lowering MDD symptoms in individuals with inadequate response to monotherapy, but it is possible that LDX may help in reducing specific symptoms of MDD such as executive dysfunction, anhedonia or lethargy [5].

There are some limitations of these studies, including sample size, and early termination of study which may influence the duration of LDX exposure. Additionally, study duration may not have been long enough to show the full effect of improvements of executive functioning and neurocognitive measures on daily functioning over time.


There is indefinite current evidence of LDX augmentation in the treatment of MDD, yet it is an alternative option that should be carefully considered. More research is needed to evaluate risks and benefits of LDX augmentation in those who responded inadequately to current treatment modalities for MDD. MDD is comorbid, highly prevalent and most disabling mental illness worldwide [1] and more focus is needed to evaluate safety and efficacy of stimulants such as LDX to be used as augmentation therapy with current treatment options.


Monitoring Editor: Rikinkumar S. Patel MD, MPH

Author: Mansi Shah MD, MBA

Author Affiliation: Zucker Hillside Hospital (Glen Oaks, NY)

Correspondence on Email:

References: are available on request

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