A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials

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

Several meta-analyses and reviews of clinical trials for stimulant and non-stimulant treatments have demonstrated improvements in EL.

“These reports have been further demonstrated by several meta-analyses and reviews of clinical trials for stimulant and non-stimulant treatments (Lenzi et al., 2017; Moukhtarian et al., 2017; C. B. H. Surman & Walsh, 2022).”

• cites Lenzi et al., 2017Not matched

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

• cites Moukhtarian et al., 2017 sourceSupported
• cites C. B. H. Surman & Walsh, 2022 sourceNot checked — no full text of the source

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

Some studies have reported improvements in EL with stimulant treatment, including MPH.

“some studies have reported improvements in EL with stimulant treatment, including MPH (Baweja et al., 2021; A. C. Childress et al., 2014; López et al., 2017).”

• cites Baweja et al., 2021 sourceSupported
• cites A. C. Childress et al., 2014 sourceNot checked — no full text of the source
• cites López et al., 2017 sourceNot checked — no full text of the source

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

Several meta-analyses and reviews assessing double-blind randomized control trials describe positive emotional outcomes for treatments such as atomoxetine, lisdexamfetamine, methylphenidate transdermal system, and OROS-MPH versus placebo in adults with ADHD.

“several meta-analyses and reviews assessing the results of double-blind randomized control trials describe positive emotional outcomes for treatments such as atomoxetine, lisdexamfetamine, methylphenidate transdermal system, and OROS-MPH versus placebo in adults with ADHD (Lenzi et al., 2017; Moukhtarian et al., 2017; C. B. H. Surman & Walsh, 2022)”

• cites Lenzi et al., 2017Not matched

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

• cites Moukhtarian et al., 2017 sourceSupported
• cites C. B. H. Surman & Walsh, 2022 sourceNot checked — no full text of the source

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

Other studies indicate that medications may blunt emotions and make individuals more irritable, with irritability contributing to the onset and worsening of EL.

“However, other studies indicate that medications may blunt emotions and make individuals more irritable, with irritability contributing to the onset and worsening of EL; this can however be altered by changing a patient’s medication formulation (Ahmann et al., 1993; Gillberg et al., 1997; Kratochvil et al., 2007; Perwien et al., 2008; Posner et al., 2014).”

• cites Ahmann et al., 1993 sourceNot checked — no full text of the source
• cites Gillberg et al., 1997Not matched

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

• cites Kratochvil et al., 2007 sourcePartly supported

  The Introduction (p. 4) describes affective blunting and mood lability as possible medication-related changes in children with ADHD. The Discussion (p. 11) suggests that changing medication may improve adverse emotional effects. Neither passage says that medication increases irritability or that irritability causes the onset or worsening of emotional lability. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

The severity of emotional and behavioral changes positively correlates with ADHD symptom severity, particularly in individuals with hyperactive-impulsive subtype, impacting social, daily living, and adaptive skills.

“the severity of these emotional and behavioral changes has been observed to positively correlate with ADHD symptom severity, particularly in individuals who exhibit the hyperactive-impulsive sub-type of ADHD, impacting social, daily living, and adaptive skills (Anastopoulos et al., 2011; Sobanski et al., 2010).”

• cites Anastopoulos et al., 2011 sourcePartly supported

  The Results (page unavailable) associate higher emotional lability with poorer social skills, daily functioning, and adaptive functioning. They do not establish a correlation with ADHD symptom severity, and they find emotional lability was more likely in the combined subtype than in the hyperactive-impulsive subtype. The findings concern children, not individuals generally. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Sobanski et al., 2010 sourcePartly supported

  The ‘Association of emotional lability with demographic and clinical characteristics’ section reports that ADHD symptom severity rises with emotional lability, more markedly for hyperactive-impulsive than inattentive symptoms; its table also reports greater social/peer problems. But the study concerns children with ADHD combined type, not specifically the hyperactive-impulsive subtype, and the cited passages do not establish effects on daily living or adaptive skills. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

EL is common in children, youth, and adults with ADHD, with parent-reported prevalence rates ranging from 11% to 47%.

“EL is common in children, youth, and adults with ADHD, with parent-reported prevalence rates ranging from 11% to 47% (Anastopoulos et al., 2011; Skirrow & Asherson, 2013; Stringaris & Goodman, 2009);”

• cites Anastopoulos et al., 2011 sourcePartly supported

  The Results report high emotional lability in 46.92% of children with ADHD, and the Method > Measures section says emotional lability was measured using parent-completed ratings. This supports the approximately 47% endpoint in children, but this paper does not establish the 11% endpoint or prevalence in youth and adults. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Skirrow & Asherson, 2013 sourceNot checked — no full text of the source
• cites Stringaris & Goodman, 2009 sourceNot checked — no full text of the source

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

ADHD combined with severe EL increases the likelihood of certain comorbidities, such as oppositional defiant, affective, and substance use disorders.

“Additionally, ADHD combined with severe EL increases the likelihood of certain comorbidities, such as oppositional defiant, affective, and substance use disorders, which make identifying an appropriate treatment regime more challenging due to varying symptom profiles and complex medication regimens (Jensen et al., 2001; Sobanski et al., 2010).”

• cites Jensen et al., 2001 sourceNot checked — no full text of the source
• cites Sobanski et al., 2010 sourceSupported

Classified as probably not a substantial claim.

The relationship between stimulant treatment and EL in individuals with ADHD remains unclear.

“however the relationship between stimulant treatment and EL in individuals with ADHD remains unclear (Posner et al., 2014).”

• Also stated in: § Discussion · plain

  “The relationship between stimulant treatment and EL is unclear because of significant inter-patient variability in EL in response to stimulant treatment, which makes clinical decision making difficult when EL is present; many studies imply a beneficial effect of stimulant treatment on EL while some patients experience increased irritability as a result of treatment which may induce or worsen EL (P”

• cites Posner et al., 2014 sourcePartly supported

  The Stimulant Effects on Emotional Lability section says empirical evidence is limited, and the Stimulant-Induced Irritability section calls for further replication and long-term follow-up (page numbers unavailable). But the Conclusions describe the available studies as uniformly supportive of stimulant treatment for emotional lability. Saying the relationship simply “remains unclear” captures the uncertainty while omitting that consistent positive signal. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

Children with ADHD and emotional dysregulation are more likely to see their ADHD symptoms persist into adulthood and are less likely to experience symptom remission, even when treated.

“Children with ADHD and emotional dysregulation are more likely to see their ADHD symptoms persist into adulthood and are overall less likely to experience symptom remission, even when they are treated (Biederman et al., 2012).”

• cites Biederman et al., 2012 sourcePartly supported

  The Discussion reports that deficient emotional self-regulation was associated with a more persistent course of ADHD, and the Results report an association between persistent ADHD and emotional dysregulation at follow-up. But follow-up was into adolescence, not adulthood, and the paper does not establish the claim's “even when treated” qualification. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

Studies with DR/ER-MPH have shown significant improvements in ADHD functional impairment in both the morning and evening using validated rating scales such as the Parent Rating of Evening and Morning Behavior Scale-Revised.

“Studies with DR/ER-MPH have shown significant improvements in ADHD functional impairment in both the morning and evening using validated rating scales such as the Parent Rating of Evening and Morning Behavior Scale—Revised (A. C. Childress et al., 2020; Pliszka et al., 2017).”

• cites A. C. Childress et al., 2020Not matched

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

• cites Pliszka et al., 2017 sourceSupported

May combine two claims.

As DR/ER-MPH is evening-dosed, there is no lag time between awakening and onset of effect, which reduces overall ADHD functional impairment in the early morning.

“As DR/ER-MPH is evening-dosed, there is no lag time between awakening and onset of effect, which reduces overall ADHD functional impairment in the early morning (A. C. Childress et al., 2020; Pliszka et al., 2017).”

• cites A. C. Childress et al., 2020Not matched

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

• cites Pliszka et al., 2017 sourceSupported

Classified as probably not a substantial claim.

Those with ADHD have symptoms upon awakening and throughout the entire day into the evening.

“Those with ADHD have symptoms upon awakening and throughout the entire day into the evening (Harpin, 2005).”

• cites Harpin, 2005 sourcePartly supported

  The Conclusion says ADHD symptoms are treated mainly during the school day, while early mornings before school and evenings until bedtime are frequently unaffected by treatment. This supports symptoms occurring beyond school hours, but the discussion concerns children and does not establish that everyone with ADHD has symptoms continuously from awakening through the evening. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

Individuals treated with morning-dosed stimulants report emotional lability symptoms in the mornings, including frequent temper tantrums and sudden changes to their mood and feelings.

“Individuals treated with morning-dosed stimulants report EL symptoms in the mornings, including frequent temper tantrums and sudden changes to their mood and feelings (Sallee, 2015).”

• cites Sallee, 2015 sourcePartly supported

  The Conclusions report caregiver-observed, inadequately controlled early-morning ADHD symptoms in stimulant-treated children and adolescents. The Introduction also discusses a morning irritability and loss-of-temper measure from another study. Our copy does not establish frequent temper tantrums or sudden mood and feeling changes in Sallee’s survey, and the reports came from caregivers rather than the treated individuals. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

During the open-label phase of HLD200-107, 37 participants reported 41 emotion-related TEAEs, with 24 instances mild and 17 moderate.

“During the open-label phase of HLD200-107, 37 participants reported 41 emotion-related TEAEs (9 of whom had an emotion-related condition in their medical history), with 24 instances being mild and 17 moderate;”

May combine two claims.

In HLD200-108, 67% of DR/ER-MPH and 70% of placebo participants reported Very Elevated EL scores at baseline; 11% and 19% had Average EL scores.

“In HLD200-108, 67% and 70% reported Very Elevated EL scores in the DR/ER-MPH and placebo groups, respectively at baseline; only 11% and 19% of DR/ER-MPH and placebo groups had Average EL scores (Figure 6).”

May combine two claims.

During the double-blind phase of HLD200-107, 1 participant randomized to placebo reported 1 moderate emotion-related TEAE and no participants randomized to DR/ER-MPH reported emotion-related TEAEs.

“1 participant randomized to the placebo group reported 1 moderate emotion-related TEAE during the double-blind phase and no participants randomized to DR/ER-MPH reported emotion-related TEAEs during the double-blind phase.”

May combine two claims.

While the majority of participants experienced improved emotional lability in response to DR/ER-MPH, a small proportion did not.

“While the majority of participants experienced improved EL in response to DR/ER-MPH, a small proportion did not”

May combine two claims.

At baseline in HLD200-107, the majority of participants (62%) had Very Elevated EL scores and only 19% had Average EL scores.

“At baseline in HLD200-107, the majority of participants (62%) had Very Elevated EL scores with only 19% of participants considered to have Average (typical levels of concern) EL scores (Figure 5).”

May combine two claims.

In the present study, improvements in CGI-P EL scores increased with treatment optimization over time, with greater improvements seen in the 6-week open-label phase of HLD200-107 compared to the 3-week forced-titration design of HLD200-108.

“In the present study, improvements in CGI-P EL scores increased with treatment optimization over time, with greater improvements seen in the 6-week open-label phase of HLD200-107 compared to the 3-week forced-titration design of HLD200-108.”

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

Stimulant medications such as MPH are known to be effective treatments for ADHD.

“Stimulant medications such as methylphenidate (MPH) are known to be effective treatments for ADHD (Biederman et al., 2003)”

• cites Biederman et al., 2003 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

In HLD200-108, an ANCOVA model was used to determine significance of the difference between DR/ER-MPH and placebo group scores, with treatment as main effect and study center and baseline score as covariates.

“An ANCOVA model was used to determine significance of the difference between the DR/ER-MPH and placebo group scores, with treatment as the main effect and study center and baseline score as covariates.”

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

EL is often confused for stimulant treatment-related "rebound".

“detecting EL itself poses a unique challenge, with EL often being confused for stimulant treatment-related “rebound” which refers to the worsening of symptoms, including emotional dysregulation, beyond a baseline state because of medication wearing off (Barkley et al., 1990).”

• cites Barkley et al., 1990Not matched

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

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

Several studies indicate a positive impact of stimulant and non-stimulant treatment on emotional symptoms in children and adolescents.

“while the majority of these studies target adult ADHD populations, several studies also indicate a positive impact of stimulant and non-stimulant treatment on emotional symptoms in children and adolescents (Kutlu et al., 2017; López et al., 2017; Shih et al., 2019).”

• cites Kutlu et al., 2017 sourceNot checked — no full text of the source
• cites López et al., 2017 sourceNot checked — no full text of the source
• cites Shih et al., 2019Not matched

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

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

Combination therapies such as concurrent psychotherapy and methylphenidate treatment have been shown to improve emotional lability.

“with combination therapies such as concurrent psychotherapy and MPH treatment also shown to improve EL (Faraone et al., 2019).”

• cites Faraone et al., 2019 sourceNot checked — no full text of the source

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

No imputation for missing values was performed.

“No imputation for missing values was performed.”

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

CGI-P at Week 3 was pre-specified as an exploratory endpoint in HLD200-108.

“CGI-P at Week 3 was pre-specified as an exploratory endpoint”

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

In HLD200-108, 161 children were included in the safety and ITT populations (DR/ER-MPH n = 81; placebo n = 80).

“In HLD200-108, 163 children were enrolled and 161 were included in the safety and ITT populations (DR/ER-MPH, n = 81; placebo, n = 80).”

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

HLD200-108 included a 3-week randomized, placebo-controlled test phase.

“HLD200-108 was a parallel-group, forced-dose titration trial of DR/ER-MPH in children with ADHD conducted in two phases: a screening/washout phase lasting up to 2 weeks followed by a 3 weeks, randomized, placebo-controlled test phase.”

Classified as probably not a substantial claim.

Definitive methodologies for assessing emotional lability changes in practice and clinical trials are as yet unestablished.

“definitive methodologies for assessing EL changes in practice and clinical trials are as yet unestablished (Manos et al., 2011)”

• cites Manos et al., 2011 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

HLD200-107 included a 1-week double-blind, randomized, placebo-controlled, parallel-group phase.

“HLD200-107 was a parallel-group, laboratory classroom study of DR/ER-MPH in children with ADHD which was conducted in three distinct phases: A screening/washout phase lasting up to 4 weeks, an open-label, treatment-optimization phase lasting 6 weeks and a 1 week double-blind, randomized, placebo-controlled, parallel-group phase ending with a laboratory classroom test day.”

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

In HLD200-107, 117 participants were included in the intent-to-treat efficacy analysis (DR/ER-MPH n = 64; placebo n = 53).

“A total of 125 children were enrolled (enrolled safety population) in HLD200-107, 119 were randomized to either DR/ER-MPH or placebo (randomized safety population), and 117 were included in the efficacy analysis (intent-to-treat [ITT] population; DR/ER-MPH, n = 64; placebo, n = 53).”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The observed improvements in emotional lability could also lead to an improved home environment, for example improved parent-child and/or family relationships.

“thus, the observed improvements in EL could also lead to an improved home environment (eg, improved parent-child and/or family relationships).”

May combine two claims.

The CGI-P EL subscale is one of few validated scales developed to assess emotional lability and offers a simple yet comprehensive three-item measurement of emotional lability severity.

“The CGI-P EL subscale is one of few validated scales developed to assess EL (Faraone et al., 2019) and offers a simple yet comprehensive three-item measurement of EL severity.”

• cites Faraone et al., 2019 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Routine scales used in pediatric practice to assess ADHD may include some degree of emotional assessment, but they lack validated subscales to determine emotional lability.

May combine two claims.

The CGI-P EL subscale is parent-rated, so emotional lability is being measured at times of day when parents are interacting with their children.

“As the scale is parent-rated, EL is being measured at times of day when parents are interacting with their children”

May combine two claims.

DR/ER-MPH has a smooth pharmacokinetic profile whereby the active ingredient is biologically available upon awakening and throughout the entire day, with a prolonged elimination phase such that >50% of methylphenidate absorption occurs after peak plasma concentrations are reached.

“DR/ER-MPH has a smooth pharmacokinetic profile whereby the active ingredient is biologically available upon awakening and throughout the entire day, with a prolonged elimination phase such that >50% of MPH absorption occurs after peak plasma concentrations are reached (A. Childress et al., 2018).”

• cites A. Childress et al., 2018Not matched

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

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

ADHD symptoms vary from individual to individual, but may include emotional lability.

“These symptoms vary from individual to individual, but may include EL (A. C. Childress & Sallee, 2015).”

• cites A. C. Childress & Sallee, 2015 sourceNot checked — no full text of the source

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

Most morning-dosed stimulant medications have a lag time between administration and effect, which results in mornings being more difficult for the individual with ADHD but also for their caregivers/families.

“Most morning-dosed stimulant medications having a lag time between administration and effect, which results in mornings being more difficult for the individual with ADHD but also for their caregivers/families (A. C. Childress et al., 2023).”

• cites A. C. Childress et al., 2023Not matched

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

Classified as probably not a substantial claim.

The application of T-scores to raw CGI-P EL data can provide useful clinical insight as to the level of emotional lability relative to non-ADHD peers, improving the scale's clinical utility.

“the application of T-scores to raw CGI-P EL data can also provide useful clinical insight as to the level of EL relative to non-ADHD peers, improving the scale’s clinical utility.”