Lisdexamfetamine Dimesylate Augmentation in Adults With Persistent Executive Dysfunction After Partial or Full Remission of Major Depressive Disorder

Only a subset of individuals with depression experience cognitive dysfunction.

“only a subset of individuals with depression experience cognitive dysfunction (Grant et al, 2001;Iverson et al, 2011)”

• cites Grant et al, 2001 sourcePartly supported

  The Discussion reports little significant cognitive impairment in younger depressed outpatients, while noting more consistent impairment in older patients and possible deficits with later onset or marked illness severity. This supports variation in cognitive functioning among people with depression, but the study does not establish that only a subset of all individuals with depression experience dysfunction. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Iverson et al, 2011 sourceSupported

In the regression model for MADRS total score change from baseline to week 9/end of study, the coefficient of change in BRIEF-A GEC T score was statistically significant (estimate, 0.21; t-statistic, 7.33; P<0.0001).

“Additionally, the coefficient of change in BRIEF-A GEC T score was statistically significant (estimate, 0.21; t-statistic, 7.33; Po0.0001), but the analysis showed that there was no differential effect of treatment with LDX vs treatment with placebo (t-statistic, -0.41; P ¼ 0.6818).”

In the regression model for MADRS total score change from baseline to week 9/end of study with BRIEF-A GEC T score change as a covariate, there was no differential effect of treatment with LDX versus placebo (t-statistic, -0.41; P = 0.6818).

“Additionally, the coefficient of change in BRIEF-A GEC T score was statistically significant (estimate, 0.21; t-statistic, 7.33; Po0.0001), but the analysis showed that there was no differential effect of treatment with LDX vs treatment with placebo (t-statistic, -0.41; P ¼ 0.6818).”

In the regression model for MADRS total score change from baseline to week 9/end of study with CNS Vital Signs NCI score change as a covariate, there was a differential effect of treatment (t-statistic, -2.66; P = 0.0090).

“There was a differential effect of treatment (t-statistic, À 2.66; P ¼ 0.0090); the coefficient for change in CNS Vital Sign NCI score was not significant (estimate, 0.03; t-statistic, 0.69; P ¼ 0.4885).”

In adults with mild major depressive disorder and persistent executive dysfunction despite partial or full remission, lisdexamfetamine dimesylate augmentation of antidepressant monotherapy significantly reduced BRIEF-A Informant Report Global Executive Composite T scores from baseline to week 9/end of study compared with placebo.

“The mean ± SD change in BRIEF-A Informant Report GEC T score from baseline to week 9/EOS was À 3.0±9.29 with placebo and À 9.6±11.94with LDX.The LS mean (95% CI) treatment difference significantly favored LDX ( À 5.9 ( À 9.3, À 2.6); |t 128 | ¼ 3.53, P ¼ 0.0006).”

In adults with mild major depressive disorder and persistent executive dysfunction despite partial or full remission, lisdexamfetamine dimesylate augmentation did not significantly improve objective cognitive functioning as assessed by the CNS Vital Signs Neurocognitive Index at week 9/end of study compared with placebo.

“On the CNS Vital Signsderived NCI, median (range) standardized scores increased from baseline (placebo, 99.5 (54, 117); LDX, 96.0 (40, 117)) to week 9/EOS (placebo, 100.0 (33, 118); LDX, 103.0 (73, 121)); there were no significant treatment differences in median NCI standardized scores at week 9/EOS (Wilcoxon rank sum test: Z ¼ 1.788, P ¼ 0.0738).”

In this trial, changes from baseline to week 9/end of study in MADRS total score and BRIEF-A Self-Report Global Executive Composite T score were strongly correlated (r2 = 0.30).

“Using the linear regression model for the MADRS total score changes from baseline to week 9/EOS with treatment group and BRIEF-A GEC T score changes from baseline to week 9/EOS as a covariate revealed that the MADRS total score and BRIEF-A GEC T score changes from baseline to week 9/EOS were strongly correlated (r 2 ¼ 0.30).”

In adults with mild major depressive disorder and persistent executive dysfunction despite partial or full remission, lisdexamfetamine dimesylate augmentation of antidepressant monotherapy significantly reduced BRIEF-A Self-Report Global Executive Composite T scores from baseline to week 9/end of study compared with placebo.

“the LS mean (95% CI) treatment difference significantly favored LDX ( À 8.0 ( À 12.7, À 3.3); P ¼ 0.0009).”

• Also stated in: § Efficacy · plain

  “The primary efficacy analysis showed LS mean (95% CI) GEC T score reductions of À 13.2 ( À 16.5, À 9.9) for placebo and À 21.2 ( À 24.5, À 17.9) for LDX at week 9/EOS; the LS mean (95% CI) treatment difference statistically favored LDX ( À 8.0 ( À 12.7, À 3.3); |t 140 | ¼ 3.38, P ¼ 0.0009).”

In this trial, changes from baseline to week 9/end of study in CNS Vital Signs Neurocognitive Index score and MADRS total score were not correlated (r2 = 0.06).

“Post hoc regression analysis revealed that NCI score and MADRS total score changes at week 9/EOS were not correlated (r 2 ¼ 0.06).”

In adults with mild major depressive disorder and persistent executive dysfunction despite partial or full remission, lisdexamfetamine dimesylate augmentation of antidepressant monotherapy significantly reduced MADRS total scores from baseline to week 9/end of study compared with placebo.

“The LS mean (95% CI) treatment difference for MADRS total score also significantly favored LDX ( À 1.9 ( À 3.7, 0.0); P ¼ 0.0465).”

• Also stated in: § BRIEF-A Informant Report. · plain

  “Changes in LS mean (95% CI) MADRS total scores from baseline to week 9/EOS were À 3.1 ( À 4.4, À 1.8) with placebo and À 5.0 ( À 6.3, À 3.6) with LDX; the LS mean (95% CI) treatment difference significantly favored LDX ( À 1.9 ( À 3.7, 0.0); |t 140 | ¼ 2.01, P ¼ 0.0465).”

In the regression model for MADRS total score change from baseline to week 9/end of study with CNS Vital Signs NCI score change as a covariate, the coefficient for change in CNS Vital Signs NCI score was not significant (estimate, 0.03; t-statistic, 0.69; P = 0.4885).

“There was a differential effect of treatment (t-statistic, À 2.66; P ¼ 0.0090); the coefficient for change in CNS Vital Sign NCI score was not significant (estimate, 0.03; t-statistic, 0.69; P ¼ 0.4885).”

In this trial, treatment-emergent adverse event rates were 73.6% with placebo and 78.9% with lisdexamfetamine dimesylate.

“TEAE rates were 73.6% with placebo and 78.9% with LDX; serious TEAE rates were 4.2 and 2.8%.”

• Also stated in: § Safety and Tolerability · plain

  “TEAE rates were 73.6% with placebo and 78.9% with LDX.”

Post hoc analyses found that changes in MADRS total score and BRIEF-A GEC T score were not independent.

“Post hoc analyses noted that changes in MADRS total score and BRIEF-A GEC T score were not independent”

The most frequently reported treatment-emergent adverse events were headache and dry mouth with placebo and decreased appetite, headache, dry mouth, insomnia, and irritability with lisdexamfetamine dimesylate.

“TEAEs reported by X5% of participants in either treatment group are summarized in Table 2; those reported most frequently were headache and dry mouth with placebo and decreased appetite, headache, dry mouth, insomnia, and irritability with LDX.”

There were no results of concern on the Sheehan Suicidality Tracking Scale.

“There were no results of concern on the STS; participants had low mean ± SD scores at baseline (placebo, 0.0 ± 0.12; LDX, 0.1 ± 0.39) and showed virtually no change throughout double-blind and single-blind treatments.”

Post hoc analyses found that MADRS total score and CNS Vital Sign NCI change scores were independent.

“MADRS total score and CNS Vital Sign NCI change scores were independent, although relatively smaller sample size may have limited our ability to definitively assess this relationship.”

Results from the ACSA during single-blind placebo treatment showed no evidence of adverse withdrawal effects.

“Results from the ACSA during single-blind placebo treatment showed no evidence of adverse withdrawal effects.”

In participants with partially to fully remitted major depressive disorder and executive dysfunction, lisdexamfetamine dimesylate augmentation produced significantly greater improvements in executive function than placebo, as measured by BRIEF-A Self-Report GEC T scores.

“Participants with partially to fully remitted MDD and executive dysfunction exhibited significantly greater improvements in executive function with LDX augmentation compared with placebo, as measured by BRIEF-A Self-Report GEC T scores.”

Vital sign and physical examination changes were generally modest with both treatments.

“Vital sign and physical examination changes were generally modest with both treatments (Table 3).”

From baseline to week 9/end of study, the mean percentage change in BRIEF-A Self-Report GEC T score was -17.0% with placebo and -28.1% with lisdexamfetamine dimesylate.

“From baseline to week 9/EOS, the mean±SD percentage change in GEC T score was À 17.0 ± 18.09% with placebo and À 28.1 ± 18.07% with LDX.”

Some individuals with major depressive disorder report considerable executive dysfunction despite having only mild depressive symptoms.

“Overall, these findings indicate that some individuals with MDD report considerable executive dysfunction despite having only mild depressive symptoms; this self-reported dysfunction was ameliorated by LDX augmentation.”

Residual depressive symptoms were significantly improved by LDX augmentation.

“In addition to improvements in cognitive function, residual depressive symptoms were also significantly improved by LDX augmentation”

There were no unexpected safety concerns.

“Overall, there were no unexpected safety concerns.”

LDX augmentation did not produce statistically superior improvement compared with placebo on the performance-based computerized test of neurocognitive function (CNS Vital Signs).

“for the other secondary cognitive end point, a performance-based computerized test of neurocognitive function, the improvement seen with LDX was not statistically superior to placebo.”

Shifts in BRIEF-A GEC T scores to within 1 SD of the normative sample mean were observed.

“By study end, mean Self-Report GEC T score with LDX augmentation was reduced to levels below the operationally defined inclusion criteria and shifts in BRIEF-A GEC T scores to within 1 SD of the normative sample mean were observed.”

The ANCOVA model-based effect size (95% CI) at week 9/end of study (LDX-placebo) was -0.6 (-0.9, -0.2).

“The ANCOVA model-based effect size (95% CI) at week 9/EOS (LDXplacebo) was À 0.6 ( À 0.9, À 0.2).”

Statistically significant LS mean treatment differences between placebo and LDX in BRIEF-A Self-Report GEC T score were observed at weeks 5-9.

“Statistically significant LS mean treatment differences between placebo and LDX were observed at weeks 5-9 (all |t 140 |41.9771¼ t 0.025,140 ; all Po0.05, Figure 2).”

By study end, mean Self-Report GEC T score with LDX augmentation was reduced to levels below the operationally defined inclusion criteria.

“By study end, mean Self-Report GEC T score with LDX augmentation was reduced to levels below the operationally defined inclusion criteria and shifts in BRIEF-A GEC T scores to within 1 SD of the normative sample mean were observed.”

The most common adverse events with LDX were decreased appetite, headache, dry mouth, and insomnia.

“The most common adverse events with LDX, including decreased appetite, headache, dry mouth, and insomnia, were similar to those reported in another study of LDX augmentation to treat depressive symptoms (Trivedi et al, 2013).”

At week 9/end of study, the percentage of participants with improved symptoms (CGI-I scores of 1 or 2) was 38.9% with placebo and 60.6% with lisdexamfetamine dimesylate.

“At week 9/EOS, the percentage of participants with improved symptoms (ie, CGI-I scores of 1 (very much improved) and 2 (much improved)) was 38.9% with placebo and 60.6% with LDX.”

Post hoc analyses of all baseline demographic, patient clinical characteristics, and pivotal assessments reported only one significant difference, which was mean citalopram usage before augmentation.

“post hoc analyses of all baseline demographic, patient clinical characteristics, and pivotal assessments reported only one significant difference, which was mean citalopram usage before augmentation.”

The CNS Vital Signs computerized testing battery is validated.

“Secondary cognitive end points included changes from baseline to week 9/EOS in BRIEF-A Informant Report GEC T score, which complemented the Self-Report, and in the performance-based Neurocognitive Index (NCI) derived from the validated, computerized CNS Vital Signs testing battery.The CNS Vital Signs comprise seven neuropsychological tests (Gualtieri and Johnson, 2006).”

• cites Gualtieri and Johnson, 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The safety profile of lisdexamfetamine dimesylate augmentation in this trial was consistent with prior studies of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

“The safety profile of LDX was consistent with prior studies in adults with attention-deficit/hyperactivity disorder.”

The BRIEF-A Self-Report provides some degree of ecological validity, an approximation of the real-world experience.

“Thus, a self-report provides some degree of ecological validity (an approximation of the real-world experience) (Isquith et al, 2013), with objective end points (ie, CNS Vital Signs data) placing the subjective data in perspective.”

• cites Isquith et al, 2013 sourceNot checked — no full text of the source

Even when depressive symptoms abate, cognitive problems may persist in individuals with major depressive disorder.

“Even when depressive symptoms abate, cognitive problems may persist (Preiss et al, 2009;Reppermund et al, 2009), compromising an individual's coping ability (Gualtieri et al, 2006) and likelihood of successfully returning to work (Reppermund et al, 2009).”

• cites Preiss et al, 2009 sourceNot checked — no full text of the source
• cites Reppermund et al, 2009 sourceNot checked — no full text of the source

Norepinephrine and dopamine are critical to maintain executive functions mediated by the prefrontal cortex.

“Norepinephrine (NE) and dopamine (DA) are critical to maintain executive functions mediated by the prefrontal cortex (Arnsten and Li, 2005); thus, agents that modulate these systems may ameliorate executive dysfunction in MDD.”

• cites Arnsten and Li, 2005 sourceNot checked — no full text of the source

Antidepressant pharmacotherapy does not always result in remission in major depressive disorder.

“Antidepressant pharmacotherapy does not always result in remission.”

• cites Rush et al, 2006 sourceNot checked — no full text of the source

The study duration may not have been long enough to show the full impact of improvements on daily functioning over time.

“the study duration may not have been long enough to show the full impact of these improvements on daily functioning over time.”

BRIEF-A and performance-based measures of executive function typically have only modest correlations.

“because there are typically only modest correlations between BRIEF-A and performance-based measures of executive function (Isquith et al, 2013), this finding is not surprising.”

• cites Isquith et al, 2013 sourceNot checked — no full text of the source

Previous studies of pharmacotherapy for cognitive or executive dysfunction in major depressive disorder have reported somewhat inconsistent findings.

“Previous studies of the pharmacotherapy for cognitive or executive dysfunction in MDD have reported somewhat inconsistent findings (DeBattista, 2005;Ferguson et al, 2003;Herrera-Guzman et al, 2010).”

• cites DeBattista, 2005 sourceNot checked — no full text of the source
• cites Ferguson et al, 2003 sourceNot checked — no full text of the source
• cites Herrera-Guzman et al, 2010 sourceNot checked — no full text of the source

The study may have had a higher possibility to detect changes on the BRIEF-A than on the CNS Vital Signs.

“As such, the study may have a higher possibility to detect changes on the BRIEF-A than on the CNS Vital Signs.”

Observing cognitive improvement in individuals with impairment may be difficult when they are grouped with individuals who are not impaired.

“so observing cognitive improvement in individuals with impairment may be difficult when they are grouped with individuals who are not impaired.”

These inconsistencies are likely related to cognitive function usually being a secondary assessment in individuals selected for relatively severe depression with or without documented cognitive dysfunction at baseline.

“These inconsistencies are likely related to the fact that cognitive function was usually a secondary assessment in individuals selected for having relatively severe depression with or without documented cognitive dysfunction at baseline in these previous studies (Herrera-Guzman et al, 2010;Raskin et al, 2007).”

• cites Herrera-Guzman et al, 2010 sourceNot checked — no full text of the source
• cites Raskin et al, 2007 sourceNot checked — no full text of the source

A population selected for high BRIEF-A GEC T scores may not have exhibited the same level of impairment on the CNS Vital Signs test battery.

“a population specifically selected for having high BRIEF-A GEC T scores may not have exhibited the same level of impairment on the CNS Vital Signs test battery.”

Executive dysfunction creates significant problems in coping with life events.

“Of particular interest in MDD are executive function deficits (Reppermund et al, 2009), which comprise higher-order functions such as problem solving, goal setting, planning, and sequencing actions (Elliott, 2003), because it creates significant problems in coping with life events (Marazziti et al, 2010).”

• cites Marazziti et al, 2010 sourceNot checked — no full text of the source

The ability of stimulants to alleviate executive dysfunction is likely related to their modulation of cortical dopaminergic and adrenergic systems.

“the ability of stimulants to alleviate executive dysfunction is likely related to their modulation of cortical dopaminergic and adrenergic systems (Arnsten and Li, 2005;Elliott, 2003).”

• cites Arnsten and Li, 2005 sourceNot checked — no full text of the source
• cites Elliott, 2003 sourceNot checked — no full text of the source

Executive function improvements were clinically relevant.

“This suggests that executive function improvements were clinically relevant.”

By including only individuals with mild depressive symptoms, it is possible to assess changes in executive and cognitive function relatively independent of depressive symptoms.

“Thus, by including only those individuals with mild depressive symptoms, it is possible to assess changes in executive and cognitive function relatively independent of depressive symptoms.”

• AssumptionRests on an assumption: Cognitive problems may be exacerbated in those with more severe depression and improve when depressive symptoms abate.

Individuals with major depressive disorder exhibit hypoactivation in the prefrontal and anterior cingulate cortices.

“individuals with MDD exhibit hypoactivation in the prefrontal and anterior cingulate cortices (Rogers et al, 2004)”

• cites Rogers et al, 2004 sourceNot checked — no full text of the source

The findings support previous evidence that dopaminergic agents can mitigate cognitive dysfunction.

“Overall, these findings support previous evidence of the ability of dopaminergic agents to mitigate cognitive dysfunction (Killgore et al, 2008;Schachar et al, 2008).”

• cites Killgore et al, 2008 sourceNot checked — no full text of the source
• cites Schachar et al, 2008 sourceNot checked — no full text of the source

The consistent observation of superiority of LDX over placebo across self-reports and informant reports provides additional support for the positive findings.

“the consistent observation of superiority of LDX over placebo across self-reports and informant reports provides additional support for our positive findings.”