Elsevier

Journal of Affective Disorders

Volume 226, 15 January 2018, Pages 294-300
Journal of Affective Disorders

Research paper
Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: A meta-analysis of randomized controlled trials

https://doi.org/10.1016/j.jad.2017.09.041Get rights and content

Highlights

  • First meta-analysis of the stimulant Lisdexamfetamine (LDX) as antidepressant augmentation.

  • The degree of improvement in depressive symptoms was consistent with a small effect.

  • No superiority in depression remission or response rates with LDX over placebo.

  • LDX associated with the same rates of SAEs and discontinuation rates as placebo.

  • Further studies are needed to determine the role of LDX in the treatment of MDD.

Abstract

Background

Psychostimulants have been used in the treatment of depression, with mixed results. This meta-analysis examines the efficacy and tolerability of the stimulant Lisdexamfetamine (LDX) as an add-on strategy in those with MDD who have failed to respond to an antidepressant.

Method

Randomized control trials were identified and extracted from Pubmed; Web of Science; PsychINFO; and Cochrane Library. The efficacy of LDX was evaluated using Hedges’ g and Odds Ratio, whereas Risk Difference was used to assess the safety and tolerability of LDX.

Results

Four studies met inclusion criteria. LDX did not demonstrate superiority in efficacy relative to placebo as indicated by a Hedges’ g score of 0.126 (95% CI −0.040–0.291; p = 0.136) for mean change in Montgomery-Asberg Depression Rating Scale. Odds ratios of 1.206 (95% CI 0.745–1.954; p = 0.446) and 1.244 (95% CI 0.959–1.614; p = 0.1) were found for remission and response rates respectively. Risk differences of −0.1 (95% CI −0.155–(−0.045); p < 0.001) indicated a 10% increase chance of developing treatment-emergent adverse events (TEAE) in the LDX group. There was no significant difference in risk for developing serious or severe TEAE and discontinuing treatment due to TEAE.

Limitations

The number of included studies was small and only one metric was available for analysis of antidepressant efficacy of LDX.

Conclusions

LDX when used as antidepressant augmentation produced a small effect in improving depressive symptoms that approached trend-level significance and demonstrated comparable tolerability to placebo. Further studies are needed to determine the optimal clinical subset of depressive symptoms responsive to LDX augmentation.

Introduction

It has become increasingly recognized that in patients with MDD who fail to achieve full symptomatic remission of their mood symptoms with an antidepressant medication, the presence of residual symptoms portends chronicity of illness. Results from the STAR*D trial indicate that amongst those who met criteria for remission after a course of antidepressant monotherapy with citalopram, more than 90% continued to endorse one or more depressive symptom, with the median number of residual symptoms being three (Nierenberg et al., 2010). In prospective studies, patients without full resolution of their MDD symptoms, experienced earlier and more frequent rates of relapse (Nierenberg et al., 2010, Paykel et al., 1995, Judd et al., 1998), and in the long-term experienced shorter periods of wellness compared with patients who were asymptomatic after treatment of an index episode of depression (Judd et al., 2000). Furthermore, incomplete response to antidepressant medication is associated with worse patient-related outcomes including quality of life and work productivity (Trivedi et al., 2009, Tranter et al., 2002, Mintz et al., 1992). Consequently, it is paramount to aggressively target and treat residual symptoms in patients with mood disorders who have achieved an incomplete resolution of their symptoms.

One potential treatment option in patients with MDD who have residual symptoms is the adjunctive use of psychostimulant medications. Despite the historical interest in the use of psychostimulants for depression which dates back to the time of their synthesis (Robin and Wiseberg, 1958), the published literature on its efficacy in MDD is inconclusive. A Cochrane systematic review concluded that there was little data to support the use of psychostimulants as an antidepressant augmentation strategy (Candy et al., 2008).

Lisdexamfetamine dimesylate (LDX), a newer psychostimulant which is approved for use in the treatment of ADHD, may offer advantages over other compounds in its class in the treatment of residual depressive symptoms. LDX is the first available prodrug stimulant, which following oral administration is enzymatically converted from a pharmacologically inactive prodrug to long-acting dexamfetamine (d-AMP) (Pennick, 2010) Pharmacokinetic data on LDX reveal that this compound provides a gradual rather than a rapid release of d-AMP throughout the day (Ermer et al., 2010). The absence of an early sharp spike in systemic concentrations of d-AMP following LDX administration and the requirements for LDX to be converted from inactive prodrug to d-AMP in the body, have been associated with the lower abuse potential compared with immediate-release stimulant preparations (Jasinski et al., 2009). LDX is associated with similar rates of treatment-emergent side-effects compared to other stimulants (Coghill et al., 2014). Furthermore, in vitro analyses have found that LDX has limited cytochrome p450 inhibition potential (Krishnan, 2007), minimizing the risk of drug-drug interactions when used in concert with other psychotropic medication as augmentation. These lines of evidence suggest that LDX merits evaluation in the treatment of residual symptoms of depression. The goal of this paper to conduct a meta-analysis examining the efficacy and tolerability of LDX as an add-on strategy to an antidepressant in those with MDD.

Section snippets

Methods

A systematic search of the literature was conducted in Pubmed, PsycINFO, Web of Science and the Cochrane Library databases for studies investigating the efficacy of lisdexamfetamine augmentation therapy in treating depression. For optimal identification of relevant studies the search strategy used a combination of the following words and phrases: (lisdexamfetamine OR Vyvanse) AND (depression OR major depression). This strategy was used for searching all of the aforementioned databases. There

Results

Our search strategy yielded a total of 97 studies. We retrieved 15 studies, of which a total of 3 were ultimately included in the meta-analysis (Fig. 1).

Mean change in MADRS score

All studies reported mean MADRS score changes from LDX augmentation baseline to end of treatment and were included in the meta-analysis (Fig. 2). A total of 946 patients (nLDX = 469; nplacebo = 477) were included in this analysis. The summary effect size (Hedges’ g) was 0.126 (95% CI – 0.040–0.291). An I2 value of 36% (p = 0.199) indicated low between study heterogeneity. After adjusting for publication bias using the trim and fill procedure the summary effect size became 0.08 (95% CI

Treatment emergent adverse events (TEAE)

Three studies reported TEAE rates following lisdexamfetamine augmentation therapy (Fig. 5). A total of 1 142 patients (nLDX = 571; nplacebo = 571) were included in this analysis. The summary risk difference effect size was −0.1 (95% CI −0.155–(−0.045)). An I2 value of 0% (p = 0.535) indicated low between- study heterogeneity. After adjusting for publication bias using the trim and fill procedure the summary risk difference remained the same.

There were no differences between LDX and placebo in

Discussion

This meta-analysis of LDX as an add-on strategy failed to demonstrate superiority in treating depressive symptoms in patients with MDD, compared to placebo. These findings are generally consistent with published trials of other long-acting psychostimulant preparations (Patkar et al., 2006, Ravindran et al., 2008). The magnitude of effect of LDX on depressive symptoms seen in our meta-analysis was small (Hedges’ g = 0.122; 95% CI −0.023–0.268) (Cohen, 1992), approaching statistical significance

Acknowledgments

Drs. PG, RL, RM and SHK acknowledge support from the Canadian Biomarker Integration Network for Depression and the Ontario Brain Institute. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred.

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