CoChat
Sign Up
Cited by 20Treatment of Major DepressionBipolar Disorder and TreatmentElectroconvulsive Therapy Studies

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

Open access
Richards, Cynthia, McIntyre, Roger S., Weisler, Richard, Sambunaris, Angelo, Brawman-Mintzer, Olga, Gao, Joseph, Geibel, Brooke, Dauphin, Matthew +1 more·2016·Journal of Affective Disorders
DOI 10.1016/j.jad.2016.07.006
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported. METHODS: Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores ≥24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores ≥18 and <50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAEs). RESULTS: Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-2.3, 1.3], P=0.583). The only TEAE reported by >5% of LDX participants at twice the placebo rate in both studies was dry mouth. LIMITATIONS: Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response. CONCLUSION: Contrary to expectations, LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy.

AI snapshot

Written from the paper’s full text.

TL;DR

In two phase 3 randomized, double-blind, placebo-controlled trials, lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy did not significantly reduce MADRS total score versus placebo in adults with major depressive disorder and inadequate response to an 8-week antidepressant lead-in. LDX was associated with more treatment-emergent adverse events and greater increases in blood pressure and pulse than placebo.

Key findings

  • The primary endpoint—change in MADRS total score from augmentation baseline to week 16—did not differ significantly between LDX and placebo: treatment difference 0.1 (95% CI −1.7 to 2.0; P=0.883) in Study 1 and −0.5 (−2.3 to 1.3; P=0.583) in Study 2.
  • The key secondary endpoint, SDS total score change, also showed no significant or clinically meaningful difference: treatment difference −0.4 (−1.8 to 1.0; P=0.576) in Study 1 and −0.6 (−1.9 to 0.7; P=0.354) in Study 2.
  • Other secondary endpoints mostly showed similar findings; nominal effects were not considered statistically significant because the primary endpoint failed. In Study 2, MAF-GFI had a nominal treatment difference of −2.2 (−4.1 to −0.2; nominal P=0.031).
  • Safety: higher percentages of treatment-emergent adverse events (TEAEs) occurred with LDX than placebo, mostly mild or moderate. TEAEs reported by ≥5% of LDX participants and at twice the placebo rate were dry mouth and nasopharyngitis in Study 1, and dry mouth and decreased appetite in Study 2. No psychosis/mania or aggression TEAEs and no deaths were reported; LDX was associated with greater mean increases in pulse and blood pressure and decreases in weight/BMI.

Methods

  • Two identically designed phase 3 multicenter, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose studies. Study 1 was conducted at 76 sites across Canada, Croatia, Mexico, Spain, and the United States; Study 2 at 94 sites across the Czech Republic, Estonia, Finland, Germany, Hungary, Poland, Romania, South Africa, Sweden, and the United States. Each had a 1–4 week screening period, an 8-week single-blind antidepressant lead-in, an 8-week double-blind treatment phase (3 weeks dose optimization, 5 weeks maintenance), and a 7–9 day follow-up.
  • Adults aged 18–65 with primary nonpsychotic MDD and MADRS total score ≥24 at lead-in baseline received an SSRI or SNRI during the lead-in. Inadequate responders were randomized 1:1 to LDX or placebo if they had MADRS ≥18 at augmentation baseline and <50% reduction from lead-in baseline. LDX started at 30 mg and could be maintained, increased to 50 or 70 mg, or down-titrated to 20 mg.
  • Primary endpoint: MADRS total score change from augmentation baseline to week 16. Key secondary endpoint: SDS total score change. Efficacy was analyzed in the full analysis set using mixed-effects models for repeated measures with treatment, visit, treatment-by-visit, sex, and antidepressant class as factors and augmentation baseline score as a covariate; hypothesis testing was 2-sided at 0.05. Sample size assumed a 3-point mean difference (SD 8.1), targeting approximately 388 participants per study (194 per treatment) for 90% power.

Limitations

  • The paper states that the primary efficacy endpoint was assessed remotely by telephone using a small pool of calibrated raters; inter-rater reliability was not assessed, so variability across raters is unknown. Detailed MADRS domain/item analyses were not performed because the primary and key secondary endpoints failed, making such analyses statistically inappropriate and unreliable.
  • The paper states that participants lacked diversity (most were White and most were female), those with psychiatric comorbidities including ADHD and active medical disorders were excluded, and executive functioning was not fully examined, limiting findings to a specific MDD population and not extending to potential MDD subtypes. Treatment duration was relatively short; longer lead-in or double-blind phases might have changed response magnitude. MDD trials are susceptible to high placebo response, which could mask a therapeutic effect.
  • Evident from the text: because the primary endpoint was not statistically significant, nominal differences on secondary endpoints should not be considered statistically significant. Also, antidepressant lead-in assignment was unblinded to investigators and participants, and the sponsor did not ensure the protocol-stated antidepressant distribution was attained.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jad.2016.07.006

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 35 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Interpretationown data

    These findings do not support previously published findings of LDX augmentation for MDD based on 2 small phase 2 studies.

    “These findings do not support previously published findings of LDX augmentation for MDD based on 2 small phase 2 studies (Madhoo et al., 2014;Trivedi et al., 2013)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Madhoo et al., 2014 source
    • cites Trivedi et al., 2013 source
  • Premisecitation

    The efficacy of LDX in MDD has been investigated in small, phase 2, randomized, double-blind, placebo-controlled studies in individuals with MDD who exhibited inadequate response to antidepressant monotherapy.

    “The efficacy of LDX in MDD has been investigated in small, phase 2, randomized, double-blind, placebo-controlled studies in individuals with MDD who exhibited inadequate response to antidepressant monotherapy (Madhoo et al., 2014;Trivedi et al., 2013).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Madhoo et al., 2014 source

      The Study Design and Participants sections (pages unavailable) describe a randomized, double-blind, placebo-controlled LDX augmentation trial involving 143 adults on stable antidepressant monotherapy. But participants had persistent executive dysfunction despite partial or full remission of depressive symptoms; the paper does not characterize them as having an inadequate antidepressant response or identify this trial as phase 2. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Trivedi et al., 2013 source
  • Premisecitation

    In a separate study that focused on treating executive dysfunction in individuals with fully or partially remitted MDD (defined as MADRS total scores ≤18), LDX augmentation of SSRI monotherapy produced significantly greater reductions in MADRS total score than placebo.

    “In a separate study that focused on treating executive dysfunction in individuals with fully or partially remitted MDD (defined as MADRS total scores r18), LDX augmentation of SSRI monotherapy produced significantly greater reductions in MADRS total score than placebo (Madhoo et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Madhoo et al., 2014 source
  • Premisecitation

    A previously published study reported that LDX augmentation significantly improved self-reported and informant-reported executive dysfunction, as measured by the Behavior Rating Inventory of Executive Function-Adult Version, in participants with mild MDD.

    “Additionally, a previously published study reported LDX augmentation significantly improved self-reported and informant-reported executive dysfunction, as measured by the Behavior Rating Inventory of Executive Function-Adult Version, in participants with mild MDD (Madhoo et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Madhoo et al., 2014 source
  • Findingown data

    In both studies, higher percentages of TEAEs were reported with LDX than with placebo.

    “In both studies, higher percentages of TEAEs were reported with LDX than with placebo.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 19
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Rosenberg et al., 2013 source
    • cites Ravindran et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Psychostimulants have been investigated for use as augmentation agents in MDD since the 1950s.

    “Psychostimulants have been investigated for use as augmentation agents in MDD since the 1950s (Robin and Wiseberg, 1958).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Robin and Wiseberg, 1958 source

      The introduction describes a 1958 trial of the stimulant methylphenidate in patients with depressive states, supporting the historical point. The introduction and Selection of Cases section describe methylphenidate versus placebo alongside general outpatient management, but do not establish its use as an augmentation agent for MDD specifically. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    The phase 3 studies described in this report were more rigorously designed and better powered than the published phase 2 studies.

    “Despite these potential explanations, it is important to note that the phase 3 studies described in this report were more rigorously designed and better powered than the published phase 2 studies (Madhoo et al., 2014;Trivedi et al., 2013).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Madhoo et al., 2014 source

      The Study Design and Statistical Analysis sections (pages not available in our copy) describe Madhoo et al.’s randomized, double-blind trial and its planned 80% power for the primary comparison. They provide a basis for describing this earlier study, but do not describe the phase 3 studies or establish that those studies were more rigorously designed and better powered. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites Trivedi et al., 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Currently approved treatments for major depressive disorder (MDD), including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), effectively reduce MDD symptoms.

    “Currently approved treatments for major depressive disorder (MDD), including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), effectively reduce MDD symptoms (Arroll et al., 2005;Cipriani et al., 2009).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Arroll et al., 2005 source

      The Discussion (page not provided) concludes that SSRIs are more effective than placebo, and the Results report improvement in studies whose participants all had MDD. The meta-analysis covers SSRIs and tricyclic antidepressants in primary care, not SNRIs, so it does not support the SNRI part of the claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Cipriani et al., 2009 source

  • May combine two claims.

    Premisecitation

    Both phase 2 studies included smaller study populations and used only SSRIs as the antidepressant medication.

    “Second, both phase 2 studies included smaller study populations and used only SSRIs as the antidepressant medication (Madhoo et al., 2014;Trivedi et al., 2013).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Madhoo et al., 2014 source
    • cites Trivedi et al., 2013 source

  • May combine two claims.

    Premisecitation

    The phase 2 studies included participants with 17-item Hamilton Depression Rating Scale scores of at least 4 or with executive dysfunction and MADRS total scores of 18 or less.

    “but the phase 2 studies included participants with 17-item Hamilton Depression Rating Scale scores Z4 (Trivedi et al., 2013) or with executive dysfunction and MADRS total scores r 18 (Madhoo et al., 2014).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Trivedi et al., 2013 source
    • cites Madhoo et al., 2014 source

  • May combine two claims.

    Interpretationcitation

    The overall safety and tolerability findings observed in these studies are consistent with previously published studies of LDX augmentation for MDD and with other clinical studies of LDX for which LDX is approved for use.

    “The overall safety and tolerability findings observed in these studies are consistent with previously published studies of LDX augmentation for MDD with other clinical studies of LDX for which LDX is approved for use (Adler et al., 2008;Madhoo et al., 2014;McElroy et al., 2016;Trivedi et al., 2013Wigal et al., 2010).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Adler et al., 2008 source
    • cites Madhoo et al., 2014 source
    • cites McElroy et al., 2016 source

  • May combine two claims.

    Findingown data

    At week 16/EOS, mean SBP and DBP decreased with placebo and increased with LDX in study 1.

    “At week 16/EOS, mean SBP and DBP decreased with placebo and increased with LDX in study 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most TEAEs were mild or moderate in intensity; the frequency of severe TEAEs was low in both studies.

    “Most TEAEs were mild or moderate in intensity; the frequency of severe TEAEs was low in both studies (see footnote to Table 3 for a complete listing).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Based on the ECG, mean heart rate increases and QT duration decreases were numerically larger with LDX than with placebo in both studies.

    “Based on the ECG, mean heart rate increases and QT duration decreases were numerically larger with LDX than with placebo in both studies (Table 3).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Similar findings of no significant difference were observed for the prespecified key secondary endpoint (SDS total score) and the other secondary efficacy endpoints.

    “Similar findings were observed for the prespecified key secondary endpoint (SDS total score) and the other secondary efficacy endpoints.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In study 2, the 2 serious TEAEs (suicidal ideation in a placebo participant and accelerated hypertension in an LDX participant) were both considered related to treatment; the suicidal ideation event resulted in study withdrawal but the case of accelerated hypertension did not.

    “In study 2, the 2 serious TEAEs (suicidal ideation in a placebo participant and accelerated hypertension in an LDX participant) were both considered related to treatment; the suicidal ideation event resulted in study withdrawal but the case of accelerated hypertension did not.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The TEAEs reported by ≥5% of participants treated with LDX and at twice the rate of placebo were dry mouth and nasopharyngitis in study 1 and dry mouth and decreased appetite in study 2.

    “The TEAEs reported by Z5% of participants treated with LDX and at twice the rate of placebo were dry mouth and nasopharyngitis in study 1 and dry mouth and decreased appetite in study 2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In study 1, there were 3 serious TEAEs in the LDX group (nonsuicidal overdose of diphenhydramine, syncope, and appendicitis; none were considered treatment related by the investigator) and 7 serious TEAEs in the placebo group (suicide attempt, major depression, vertigo, syncope, appendectomy, laceration, and skin infection).

    “In study 1, there were 3 serious TEAEs in the LDX group (nonsuicidal overdose of diphenhydramine, syncope, and appendicitis; none were considered treatment related by the investigator) and 7 serious TEAEs in the placebo group (suicide attempt, major depression, vertigo, syncope, appendectomy, laceration, and skin infection).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The suicide attempt and case of major depression in study 1 were considered to be treatment related by the investigator.

    “The suicide attempt and case of major depression were considered to be treatment related by the investigator.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fridericia-corrected QT interval decreases were comparable with placebo and LDX in study 1, but were numerically larger with LDX in study 2.

    “Fridericia-corrected QT interval decreases were comparable with placebo and LDX in study 1, but were numerically larger with LDX in study 2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At least 1 suicide attempt was reported on the C-SSRS during double-blind treatment in 1 (0.5%) placebo participant in each study; the suicide attempt in study 2 was also recorded as a TEAE of mild intensity.

    “At least 1 suicide attempt was reported on the C-SSRS during double-blind treatment in 1 (0.5%) placebo participant in each study; the suicide attempt in study 2 was also recorded as a TEAE of mild intensity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean weight and BMI increased with placebo and decreased with LDX in both studies.

    “Mean weight and BMI increased with placebo and decreased with LDX in both studies (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    On the C-SSRS, at least 1 positive suicidal ideation occurred during double-blind treatment in 14 placebo (7.0%) and 14 LDX (7.0%) participants in study 1 and in 20 placebo (9.4%) and 19 LDX (9.0%) participants in study 2.

    “On the C-SSRS, Z1 positive suicidal ideation occurred during double-blind treatment in 14 placebo (7.0%) and 14 LDX (7.0%) participants in study 1 and in 20 placebo (9.4%) and 19 LDX (9.0%) participants in study 2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LDX was associated with greater mean increases in pulse rate and blood pressure than placebo and with decreases in weight and BMI.

    “LDX was associated with greater mean increases in pulse rate and blood pressure than placebo and with decreases in weight and BMI.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    The lack of efficacy observed in the current study may indicate that psychostimulants as a class are ineffective in treating undifferentiated residual depressive symptoms in individuals who exhibit an inadequate response to antidepressant monotherapy.

    “The lack of efficacy observed in the current study may indicate that psychostimulants as a class are ineffective in treating undifferentiated residual depressive symptoms in individuals who exhibit an inadequate response to antidepressant monotherapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Patkar et al., 2006 source
    • cites Postolache et al., 1999 source
    • cites Ravindran et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    An interactive voice/web response system was used to generate a randomization number, stratified by sex and antidepressant type (SSRI vs SNRI), at augmentation baseline.

    “An interactive voice/web response system was used to generate a randomization number, stratified by sex and antidepressant type (SSRI vs SNRI), at augmentation baseline.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Each study employed a multicenter, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose design.

    “Each study employed a multicenter, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose design.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Discrepancies between the current phase 3 studies and previously published phase 2 studies might be attributed to study design differences.

    “Discrepancies between the current phase 3 studies and previously published phase 2 studies might be attributed to study design differences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The phase 3 studies required that participants have MADRS total scores of at least 18 at augmentation baseline and MADRS total score reductions of no more than 50% from the antidepressant lead-in baseline to augmentation baseline.

    “The phase 3 studies required that participants have MADRS total scores of Z18 at augmentation baseline and MADRS total score reductions of o50% from the antidepressant lead-in baseline to augmentation baseline”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All study protocols were approved by ethics committees and regulatory agencies before initiating the studies, and written informed consent was obtained before performing study-related procedures.

    “All study protocols were approved by ethics committees and regulatory agencies before initiating the studies, and written informed consent was obtained before performing study-related procedures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Both studies were conducted in accordance with guidelines from the International Conference on Harmonization Good Clinical Practice and the principles of the Declaration of Helsinki.

    “Both studies were conducted in accordance with guidelines from the International Conference on Harmonization Good Clinical Practice and the principles of the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Lisdexamfetamine dimesylate (LDX) is approved in the United States and in other countries for use in patients 6 years and older with attention-deficit/hyperactivity disorder (ADHD) and for use in adults with moderate to severe binge eating disorder only in the United States.

    “Lisdexamfetamine dimesylate (LDX) is approved in the United States and in other countries for use in patients 6 years and older with attention-deficit/hyperactivity disorder (ADHD) and for use in adults with moderate to severe binge eating disorder only in the United States Vyvanse® [lisdexamfetamine dimesylate] 2015.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vyvanse® [lisdexamfetamine dimesylate] 2015

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

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    To maintain blinding, LDX capsules were over-encapsulated and appeared identical to placebo.

    “To maintain blinding, LDX capsules were over-encapsulated and appeared identical to placebo.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Based on an estimated 20% discontinuation rate during the double-blind treatment phase, approximately 388 participants (194 per treatment) were to be randomized.

    “Based on an estimated 20% discontinuation rate during the double-blind treatment phase, approximately 388 participants (194 per treatment) were to be randomized.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Assuming a 3-point mean between-group difference (SD=8.1), it was estimated that 155 participants per treatment would provide 90% power (2-sided 5% significance level).

    “Assuming a 3-point mean between-group difference (SD ¼ 8.1), it was estimated that 155 participants per treatment would provide 90% power (2-sided 5% significance level).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    After screening, eligible participants entered the 8-week single-blind antidepressant lead-in phase, which prospectively assessed response to antidepressant monotherapy and blinded participants to the time of randomization.

    “After screening, eligible participants entered the 8-week single-blind antidepressant lead-in phase, which prospectively assessed response to antidepressant monotherapy and blinded participants to the time of randomization.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The MADRS was completed by a central rater via telephone who was blinded to study visit and entry criteria.

    “Although all participants visited the study site for each visit, the MADRS was completed by a central rater via telephone (MedAvante, Inc; Hamilton, NJ) who was blinded to study visit and entry criteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Those with psychiatric comorbidities (including ADHD) and/or active medical disorders were excluded and executive functioning was not fully examined in these studies.

    “Those with psychiatric comorbidities (including ADHD) and/or active medical disorders were excluded and executive functioning was not fully examined in these studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    As inter-rater reliability was not assessed in the current studies, it is a limitation that variability across raters is unknown.

    “As inter-rater reliability was not assessed in the current studies, it is a limitation that variability across raters is unknown.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The use of telephone measures is a method now being used in clinical trials to reduce bias.

    “The use of telephone measures is a method now being used in clinical trials to reduce bias (Kobak et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kobak et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The treatment duration in the current studies was relatively short.

    “It should also be noted that the treatment duration in the current studies was relatively short.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Participants in the current studies lacked diversity in terms of race (most were White) and gender (most were female).

    “Also, participants in the current studies lacked diversity in terms of race (most were White) and gender (most were female).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    A detailed assessment of MADRS domains was not performed because the primary and key secondary endpoints consistently failed in both studies, making such assessments statistically inappropriate and unreliable.

    “However, a detailed assessment of MADRS domains was not performed because the primary and key secondary endpoints consistently failed in both studies, making such assessments statistically inappropriate and unreliable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These findings are limited to a specific MDD population and do not extend to potential MDD subtypes.

    “Therefore, these findings are limited to a specific MDD population and do not extend to potential MDD subtypes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Clinical trials for MDD are susceptible to having high placebo responses, which could mask a potential therapeutic effect.

    “Finally, clinical trials for MDD are susceptible to having high placebo responses (Walsh et al., 2002), which could mask a potential therapeutic effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Walsh et al., 2002 source
42 of 42

  • The paper relies on this without support.

    There are few medications approved by the US Food and Drug Administration for use as augmentation agents in MDD.

    “Despite the relatively high partial remission rates following antidepressant therapy, there are few medications approved by the US Food and Drug Administration for use as augmentation agents in MDD.”

  • The paper relies on this without support.

    The 2 phase 3 studies are the largest randomized clinical trials of stimulant augmentation of antidepressant therapy completed to date.

    “In conclusion, in the 2 largest, randomized clinical trials of stimulant augmentation of antidepressant therapy completed to date, LDX was not superior to placebo in reducing the depressive symptoms of MDD in individuals with inadequate responses to standard antidepressant monotherapy.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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).”

    From The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities (2018) · cites this paper as [234]

  • Evidence for the efficacy of lisdexamfetamine dimesylate augmentation therapy in adults with MDD is equivocal, with phase 2 studies reporting positive effects on residual depressive symptoms and/or symptoms of executive dysfunction but not replicated in phase 3 studies.

    “There has been equivocal evidence for the efficacy of lisdexamfetamine dimesylate augmentation therapy in adults with MDD, with phase 2 studies reporting positive effects on residual depressive symptoms [137] and/or symptoms of executive dysfunction [138] but this was not replicated in phase 3 studies [139].”

    From Adult ADHD and comorbid disorders: clinical implications of a dimensional approach (2017) · cites this paper as [139]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Richards, C., McIntyre, R. S., Weisler, R., Sambunaris, A., Brawman-Mintzer, O., Gao, J., Geibel, B., Dauphin, M., & Madhoo, M.
Affiliations
  • Shire (United States) (US)
  • University of Toronto (CA)
  • University of North Carolina at Chapel Hill (US)
  • Institute for Advanced Medical Research (US)
Corresponding author
Madhoo, Manisha
ORCID
McIntyre, Roger S.
Venue
Journal of Affective Disorders
Publisher
Elsevier BV
Published
2016-12
Volume
206
Pages
151-160
ISSN
0165-0327 (ISSN-L)
DOI
10.1016/j.jad.2016.07.006
OpenAlex
W2465070206
Semantic Scholar
6aa18fafeba9e4a1ceeb32eb69ef0f87d5bec087
Cited by
20
References
30
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 4 · 2018: 2 · 2017: 6
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Affective Disorders (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Keywords
lisdexamfetamine dimesylate, major depressive disorder, antidepressant augmentation, treatment-emergent adverse events, xerostomia, antidepressant monotherapy, treatment-resistant depression, treatment efficacy and safety, Montgomery-Asberg Depression Rating Scale, dose optimization, adults with depression, tolerability
MeSH terms
Duloxetine Hydrochloride, Venlafaxine Hydrochloride, Lisdexamfetamine Dimesylate, Adult, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Citalopram, Least-Squares Analysis, Treatment Outcome, Dopamine Uptake Inhibitors, Sertraline, Diagnostic and Statistical Manual of Mental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review