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Cited by 7Menopause: Health Impacts and TreatmentsCancer-related cognitive impairment studiesAttention Deficit Hyperactivity Disorder

Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine

Open access
Metcalf, Christina A., Page, Chloe E., Stocker, Brianna O.S., Johnson, Rachel L., Duffy, Korrina A., Sammel, Mary D., Loughead, James, Epperson, C. Neill·2024·Gynecologic Oncology
DOI 10.1016/j.ygyno.2024.07.689PMC PMC11702344
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Abstract

Objective To determine whether the psychostimulant lisdexamfetamine improves subjective and objective measures of cognitive functioning among women genetically at-risk for cancer who have undergone risk-reducing salpingo-oophorectomy and report new-onset executive functioning difficulties. Methods 69 participants were assigned to a randomized controlled crossover trial with 6-week trials of active medication (lisdexamfetamine) and placebo, separated by a minimum 2-week washout in an intent-to-treat framework (clinical trial registration number: NCT03187353). At trial baseline, midpoint, and endpoint, participants completed a self-report measure of executive functioning (Brown Attention Deficit Disorder Scale). At study baseline and trial endpoint, participants completed sustained attention, attention/working memory, and verbal learning/memory cognitive tasks. Side effects were assessed at 2, 3, 4, and 6 weeks for each trial. Results From trial baseline to trial endpoint, lisdexamfetamine - relative to placebo - significantly improved total scores on the self-report Brown Attention Deficit Disorder Scale (and scores on four of five subdomains) as well as attention and working memory performance. Significantly more participants endorsed side effects across the lisdexamfetamine trial versus placebo; however, trial completion rates were similar, indicating that lisdexamfetamine was nonetheless well-tolerated. Conclusions Lisdexamfetamine improved both subjective and objective measures of attention and working memory and could offer women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy an alternative therapeutic option.

AI snapshot

Written from the paper’s full text.

TL;DR

In a randomized, double-blind, placebo-controlled crossover trial, lisdexamfetamine improved self-reported executive functioning and attention/working memory in women with new-onset cognitive complaints after risk-reducing salpingo-oophorectomy. Effects were rapid by week 3 and accompanied by more side effects but similar trial completion rates.

Key findings

  • From trial baseline to endpoint, lisdexamfetamine reduced total Brown Attention Deficit Disorder Scale (BADDS) scores significantly more than placebo by 15.36 points (95% CI: −20.33, −10.40; p < 0.001), with significant improvement in four of five BADDS subdomains; subscale 4 was not significant (p = 0.178).
  • BADDS percent change improved more with lisdexamfetamine than placebo at endpoint (39.3% [SD 26.7] vs 2.7% [SD 49.9]; β = −37.1; 95% CI: −48.5, −25.8; p < 0.001) and at midpoint (37.0% [SD 24.2] vs 5.8% [SD 33.3]; p < 0.001).
  • Responder rates were higher with lisdexamfetamine: 49/60 (81.7%) vs 32/59 (45.8%) for placebo, with an odds ratio of 3.64 (95% CI: 2.01, 6.57; p < 0.001).
  • Lisdexamfetamine improved Letter N-back attention/working memory performance over placebo by 1.50 points (p = 0.037), but not sustained attention on the CPT (p = 0.449) or verbal learning/memory on the NYU Paragraph Recall Task (p = 0.826); more participants reported side effects in the lisdexamfetamine trial, and heart rate increases were greater at midpoint (3.80 bpm; 95% CI: 0.71, 6.91; p = 0.016) and endpoint (5.05 bpm; 95% CI: 1.90, 8.19; p = 0.002).

Methods

  • Double-blind, placebo-controlled, randomized crossover trial with 6-week trials of lisdexamfetamine and placebo separated by a minimum 2-week washout, analyzed in an intent-to-treat framework (NCT03187353).
  • Participants were women ages 35–58 who self-reported new-onset executive function difficulties after premenopausal risk-reducing salpingo-oophorectomy, scored ≥20 on the BADDS at screening, and had no exclusionary psychiatric, substance use, or medical conditions; 69 were randomized and 57 completed.
  • Outcomes included the self-report BADDS at trial baseline, midpoint, and endpoint; cognitive tasks (CPT, Letter N-back, NYU Paragraph Recall) at study baseline and trial endpoints; and side effects at 2, 3, 4, and 6 weeks per trial. Main analyses used linear mixed effects models with random intercepts, adjusted for randomization order, plus responder and side-effect models.

Limitations

  • The authors state the sample was highly educated, predominantly White (95%), married/partnered (87%), and employed (87%), so findings may not generalize to less privileged post-RRSO populations.
  • The authors note that longer-term follow-up is needed beyond the 6-week trials, and that significantly more side effects in the lisdexamfetamine condition may have unblinded participants and biased self-reported executive functioning.
  • The paper also states analyses were performed without adjustment for multiple comparisons, and sample size was not sufficient to consider a condition-by-time-by-hormone therapy/aromatase inhibitor interaction.

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

Integrity signals

Registry

Crossref · 10.1016/j.ygyno.2024.07.689

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

28 of 60 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Risk-reducing bilateral salpingo-oophorectomy lowers the likelihood of ovarian and breast cancer among women who carry BRCA1 or BRCA2 gene mutations.

    “Risk-reducing bilateral salpingo-oophorectomy (RRSO) lowers the likelihood of ovarian and breast cancer among women who carry BRCA1 or BRCA2 gene mutations”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] Domchek SM, Friebel TM, Singer CF,, Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality, Jama 304 (9) (2010) 967– 975. 20810374 PMC2948529 source
    • cites [2] Vermeulen RFM, van Beurden M, Korse CM, Kenter GG, Impact of risk-reducing salpingo-oophorectomy in premenopausal women, Climacteric 20 (3) (2017) 212– 221, 10.1080/13697137.2017.1285879. 28509627 source

      The Introduction (page unavailable) says high-risk women undergo RRSO to lower ovarian cancer risk by 80–96% and identifies BRCA1/2 carriers as eligible. The Safety of hormone replacement therapy section reports lower breast cancer risk in a cohort of BRCA1/2 carriers who underwent RRSO and took HRT than in women who had neither; it does not establish a breast cancer reduction from RRSO alone. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    RRSO leads to abrupt withdrawal of estradiol to the prefrontal cortex and hippocampus, brain regions underlying executive functions and verbal memory.

    “RRSO leads to abrupt withdrawal of estradiol to the prefrontal cortex and hippocampus, brain regions underlying executive functions (e.g., sustained attention, processing speed, working memory) and verbal memory [9].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Shanmugan S, Sammel MD, Loughead J,, Executive function after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: does current mood and early life adversity matter? Menopause 27 (7) (2020) 746– 755, 10.1097/GME.0000000000001535. 32187134 PMC7473450 source

      The Introduction (page unavailable) describes premature, abrupt loss of estradiol with RRSO and links it to executive-function difficulties. The paper discusses sustained attention and working memory, but the passages in our copy do not identify the prefrontal cortex or hippocampus as sites of estradiol withdrawal or link those regions to verbal memory. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Undergoing surgical menopause is possibly associated with increased dementia risk.

    “However, undergoing surgical menopause is associated with increased risk of cognitive complaints, cognitive performance declines, and possibly increased dementia risk, particularly if surgery occurs before age 40 or natural menopause [2–7].”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [2] Vermeulen RFM, van Beurden M, Korse CM, Kenter GG, Impact of risk-reducing salpingo-oophorectomy in premenopausal women, Climacteric 20 (3) (2017) 212– 221, 10.1080/13697137.2017.1285879. 28509627 source
    • cites [3] Rocca WA, Bower JH, Maraganore DM,, Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause, Neurology 69 (11) (2007) 1074– 1083, 10.1097/01.ogx.0000298340.04506.cc. 17761551 source
    • cites [4] Ryan J, Scali J, Carriere I,, Impact of a premature menopause on cognitive function in later life, BJOG An Int. J. Obstet. Gynaecol. 121 (13) (2014) 1729– 1739. 24802975 source
    • cites [5] Kurita K, Henderson VW, Gatz M,, Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women, Fertil. Steril. 106 (3) (2016) 749– 756, 10.1016/j.fertnstert.2016.04.033. 27183047 PMC5743432 source

      The Results report declines in some measures of cognitive performance after surgical menopause, but the study does not report dementia incidence or risk. A search for “dementia” found it in reference titles, not in a passage stating the claimed association. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [6] Henderson VW, Sherwin BB, Surgical versus natural menopause: Cognitive issues, Menopause 14 (3) (2007) 572– 579, 10.1097/gme.0b013e31803df49c. 17476147 source
    • cites [7] Evans EC, Matteson KA, Orejuela FJ,, Salpingo-oophorectomy at the time of benign hysterectomy: a systematic review, Obstet. Gynecol. 128 (3) (2016) 476– 485, 10.1097/AOG.0000000000001592. 27500347 PMC5100819 source

      The section headed “Salpingo-oophorectomy at the Time of Benign Hysterectomy: A Systematic Review” discusses mortality and accelerated aging after bilateral oophorectomy, but does not address dementia risk. Searches of our copy for dementia and cognitive impairment found no passage supporting the claimed association. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Premisecitation

    A significant proportion of the post-RRSO population does not use hormone therapy.

    “However, a significant proportion of this population does not use HT [11].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Johansen N, Liavaag AH, Iverson O-E, Dørum A, Braaten T, Michelsen TM, Use of hormone replacement therapy after risk-reducing salpingo-oophorectomy, Acta Obstet. Gynecol. Scand. 96 (2017) 547– 555, 10.1111/aogs.13120. 28236297 source
  • Premisecitation

    Among women experiencing cognitive difficulties associated with natural menopause, LDX improves executive function.

    “Among women experiencing cognitive difficulties associated with natural menopause, LDX improves executive function, including in one double-blind, placebo-controlled, crossover study [14,15].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] Shanmugan S, Loughead J, Nanga RPR,, Lisdexamfetamine effects on executive activation and neurochemistry in menopausal women with executive function difficulties, Neuropsychopharmacology 42 (2) (2017) 437– 445, 10.1038/npp.2016.162. 27550732 PMC5399233 source
    • cites [15] Epperson CN, Shanmugan S, Kim DR,, New onset executive function difficulties at menopause: a possible role for lisdexamfetamine, Psychopharmacology 232 (16) (2015) 3091– 3100, 10.1007/s00213-015-3953-7. 26063677 PMC4631394 source
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 27
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Undergoing surgical menopause is associated with increased risk of cognitive complaints and cognitive performance declines, particularly if surgery occurs before age 40 or natural menopause.

    “However, undergoing surgical menopause is associated with increased risk of cognitive complaints, cognitive performance declines, and possibly increased dementia risk, particularly if surgery occurs before age 40 or natural menopause [2–7].”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [2] Vermeulen RFM, van Beurden M, Korse CM, Kenter GG, Impact of risk-reducing salpingo-oophorectomy in premenopausal women, Climacteric 20 (3) (2017) 212– 221, 10.1080/13697137.2017.1285879. 28509627 source

      The Discussion reports lower memory-task scores after surgical than natural menopause and says scores were lower when oophorectomy occurred at a younger age. The Cognitive function section reports increased later-life impairment, with the greatest risk before age 45 among women not treated with estrogen until at least 45. The copy does not establish a specific before-40 threshold or separately report an increased risk of cognitive complaints. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [3] Rocca WA, Bower JH, Maraganore DM,, Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause, Neurology 69 (11) (2007) 1074– 1083, 10.1097/01.ogx.0000298340.04506.cc. 17761551 source
    • cites [4] Ryan J, Scali J, Carriere I,, Impact of a premature menopause on cognitive function in later life, BJOG An Int. J. Obstet. Gynaecol. 121 (13) (2014) 1729– 1739. 24802975 source
    • cites [5] Kurita K, Henderson VW, Gatz M,, Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women, Fertil. Steril. 106 (3) (2016) 749– 756, 10.1016/j.fertnstert.2016.04.033. 27183047 PMC5743432 source

      The Results (page not provided) associate surgical menopause before natural menopause with declines in specific cognitive domains, with findings differing for surgery before versus after age 45. The paper does not establish a particular threshold at age 40, and its cognitive-test outcomes do not support the claim about cognitive complaints. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] Henderson VW, Sherwin BB, Surgical versus natural menopause: Cognitive issues, Menopause 14 (3) (2007) 572– 579, 10.1097/gme.0b013e31803df49c. 17476147 source
    • cites [7] Evans EC, Matteson KA, Orejuela FJ,, Salpingo-oophorectomy at the time of benign hysterectomy: a systematic review, Obstet. Gynecol. 128 (3) (2016) 476– 485, 10.1097/AOG.0000000000001592. 27500347 PMC5100819 source

      The available text under “Salpingo-oophorectomy at the Time of Benign Hysterectomy: A Systematic Review” discusses mortality, accelerated aging, and oophorectomy before age 50 or menopause. Searches for cognitive complaints, cognitive performance, dementia, and surgery before age 40 found no passage addressing the claimed cognitive outcomes. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Cognitive performance was assessed using the CPT, LNB, and NYU Paragraph Recall Task.

    “Cognitive performance on the CPT [22] (sustained attention), LNB [23] (attention and working memory), and NYU Paragraph Recall Task [24] (verbal learning and verbal memory) were used to examine LDX’s impact on specific executive function domains.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [22] Kurtz MM, Ragland JD, Bilker W, Gur RC, Gur RE, Comparison of the continuous performance test with and without working memory demands in healthy controls and patients with schizophrenia, Schizophr. Res. 48 (2–3) (2001) 307– 316, 10.1016/S0920-9964(00)00060-8. 11295383 source
    • cites [23] Ragland JD, Turetsky BI, Gur RC,, Working memory for complex figures: an fMRI comparison of letter and fractal n-back tasks, Neuropsychology 16 (3) (2002) 370– 379, 10.1037//0894-4105.16.3.370. 12146684 PMC4332798 source
    • cites [24] Kluger A, Ferris SH, Golomb J, Mittelman MS, Reisberg B, Neuropsychological prediction of decline to dementia in nondemented elderly, J. Geriatr. Psychiatry Neurol. 12 (4) (1999) 168– 179. 10616864 source

  • May combine two claims.

    Premisecitation

    LDX represents a potential treatment option for post-RRSO women because many of their new-onset cognitive difficulties overlap with symptoms of ADHD.

    “LDX represents a potential treatment option for post-RRSO women as many of their new-onset cognitive difficulties overlap with symptoms of ADHD [9].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Shanmugan S, Sammel MD, Loughead J,, Executive function after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: does current mood and early life adversity matter? Menopause 27 (7) (2020) 746– 755, 10.1097/GME.0000000000001535. 32187134 PMC7473450 source

      The Introduction and Methods describe executive-function difficulties after RRSO and assess them with the Brown Attention Deficit Disorder Scale, supporting an overlap with ADHD-related difficulties. But the Discussion does not propose lisdexamfetamine (LDX) for post-RRSO women, and the Limitations say longitudinal data are needed to establish changes after surgery. The References mention a lisdexamfetamine study in naturally menopausal women, not a treatment study in this RRSO cohort. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Surgical menopause is associated with more severe cognitive impairments relative to natural postmenopause; younger age at surgical menopause worsens these cognitive outcomes.

    “Surgical menopause is associated with more severe cognitive impairments relative to natural postmenopause; younger age at surgical menopause worsens these cognitive outcomes [3,5,6].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [3] Rocca WA, Bower JH, Maraganore DM,, Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause, Neurology 69 (11) (2007) 1074– 1083, 10.1097/01.ogx.0000298340.04506.cc. 17761551 source
    • cites [5] Kurita K, Henderson VW, Gatz M,, Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women, Fertil. Steril. 106 (3) (2016) 749– 756, 10.1016/j.fertnstert.2016.04.033. 27183047 PMC5743432 source

      The Results and Discussion report poorer performance or decline in specific cognitive domains after surgical menopause compared with natural menopause. They do not show that younger surgical menopause uniformly worsens cognitive outcomes: surgery before and after age 45 was associated with declines in different domains, and the Results state that age at menopause itself was not associated with cognitive function. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [6] Henderson VW, Sherwin BB, Surgical versus natural menopause: Cognitive issues, Menopause 14 (3) (2007) 572– 579, 10.1097/gme.0b013e31803df49c. 17476147 source

  • Classified as probably not a substantial claim.

    Premisecitation

    In placebo-controlled LDX trials in ADHD, participants were considered treatment responders if they had a ≥ 30% reduction in ADHD symptoms using a standardized scale.

    “in placebo-controlled LDX trials in ADHD, participants were considered treatment “responders” if they had a ≥ 30% reduction in ADHD symptoms using a standardized scale [27–29].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [27] Adler LA, Goodman DW, Kollins SH,, Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder, J. Clin. Psychiatry 69 (9) (2008) 1364. 19012818 source
    • cites [28] Wigal T, Brams M, Gasior M, Gao J, Squires L, Giblin J, Randomized, double-blind, placebo-controlled, crossovercrossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design, Behav. Brain Funct. 6 (34) (2010) 1– 14. 20576091 PMC2908054 source

      The Methods (Study design; page unavailable) define an acceptable response during open-label dose optimization as a ≥30% reduction on the ADHD-RS-IV, a CGI-I rating of 1 or 2, and tolerable adverse effects. Thus, the standardized-scale threshold is supported, but a ≥30% reduction alone was not sufficient, and this classification was specified for the open-label phase rather than the placebo-controlled crossover phase. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [29] Biederman J, Petty CR, Woodworth KY, Lomedico A, Hyder LL, Faraone SV, Adult outcome of attention-deficit/hyperactivity disorder: a controlled 16-year follow-up study, J. Clin. Psychiatry 73 (7) (2012) 941– 950, 10.4088/JCP.11m07529. 22901345 source

      The Follow-Up Assessment Procedures section defines persistent and subthreshold ADHD for a 16-year follow-up study, not treatment response in a placebo-controlled trial. Searches for LDX, lisdexamfetamine, and a 30% symptom-reduction responder threshold found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    Although self-report is subject to various challenges including social desirability, recall, and response-shift biases, the BADDS has demonstrated predictive validity and utility in treatment trials, supporting its value in assessing subjective experience of executive functioning.

    “Although self-report is subject to various challenges including social desirability, recall, and response-shift biases [35], the BADDS has demonstrated predictive validity and utility in treatment trials [15], supporting its value in assessing subjective experience of executive functioning.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [35] Althubaiti A, Information bias in health research: definition, pitfalls, and adjustment methods, J. Multidiscip. Healthc. 9 (2016) 211– 217, 10.2147/JMDH.S104807. 27217764 PMC4862344 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [15] Epperson CN, Shanmugan S, Kim DR,, New onset executive function difficulties at menopause: a possible role for lisdexamfetamine, Psychopharmacology 232 (16) (2015) 3091– 3100, 10.1007/s00213-015-3953-7. 26063677 PMC4631394 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    In contrast to other amphetamines, LDX has a long-acting prodrug formulation requiring red blood cell enzymatic conversion into the active form of amphetamine, reducing side effects and abuse potential.

    “Moreover, in contrast to other amphetamines, LDX has a long-acting prodrug formulation requiring red blood cell enzymatic conversion into the active form of amphetamine, reducing side effects and abuse potential [42].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Madaan V, Kolli V, Bestha DP, Shah MJ, Update on optimal use of lisdexamfetamine in the treatment of ADHD, Neuropsychiatr. Dis. Treat. 9 (2013) 977– 983, 10.2147/NDT.S34092. 23901276 PMC3726586 source

      The Introduction and Pharmacologic aspects sections describe LDX as a longer-acting prodrug converted to dextroamphetamine by hydrolysis in red blood cells. But the paper says it *may* cause fewer adverse reactions than mixed-amphetamine extended-release salts and that its lower abuse potential is hypothesized, rather than establishing that the formulation reduces both risks. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Although ADHD is distinct from new-onset post-RRSO executive functioning problems, the management of ADHD can be informative as LDX is a preferred treatment.

    “Although ADHD is distinct from new-onset post-RRSO executive functioning problems, the management of ADHD can be informative as LDX is a preferred treatment [25,26].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [25] Cortese S, Adamo N, Del Giovane C,, Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis, Lancet Psychiatry 5 (9) (2018) 727– 738, 10.1016/S2215-0366(18)30269-4. 30097390 PMC6109107 source

      The Discussion (page not available in our copy) supports amphetamines as a first pharmacological choice for adults with ADHD and reports that NICE lists lisdexamfetamine (LDX) as a first choice. But the authors explicitly say they cannot recommend LDX over other amphetamines for adults, so the paper does not establish a specific preference for LDX. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [26] Excellence NI ffor H and C, Attention Deficit Hyperactivity Disorder: Diagnosis and Management, 2024. 10.1002/pnp.511. 29634174 source

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

    Findingown data

    No significant effects of randomization order were observed on blood pressure, heart rate, or weight.

    “No significant effects of randomization order were observed on blood pressure, heart rate, or weight;”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Those in the LDX trial were 3.64 times more likely than those in the placebo trial to be classified as responders (95% CI: 2.01, 6.57; p < 0.001).

    “Participants were more likely to be classified as responders in the LDX than placebo trial. In the responder analysis (trial endpoint BADDS <90% CI lower bound from trial baseline), the LDX trial resulted in 49/60 responders (81.7%) while the placebo trial only resulted in 32/59 responders (45.8%).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A minimum 2-week washout is sufficient to eliminate carryover effects between LDX and placebo trials.

  • May combine two claims.

    Findingown data

    In the responder analysis, the LDX trial resulted in 49/60 responders (81.7%) while the placebo trial resulted in 32/59 responders (45.8%).

    “Participants were more likely to be classified as responders in the LDX than placebo trial. In the responder analysis (trial endpoint BADDS <90% CI lower bound from trial baseline), the LDX trial resulted in 49/60 responders (81.7%) while the placebo trial only resulted in 32/59 responders (45.8%).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A minimum 2-week washout is sufficient to eliminate carryover effects between LDX and placebo trials.

  • May combine two claims.

    Findingown data

    LDX and placebo treatments did not differ at trial midpoint or endpoint for systolic or diastolic blood pressure or weight changes (ps > 0.05).

    “LDX and placebo treatments did not differ at trial midpoint (3 weeks) or endpoint (6 weeks) for systolic or diastolic blood pressure or weight changes (ps > 0.05).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    There was no significant interaction between study timepoint and history of chemotherapy for performance on the NYU Paragraph Recall Task (p = 0.803).

    “There were no significant interactions between study timepoint (study baseline, end of placebo trial, and end of LDX trial) and history of chemotherapy (yes or no) for performance on the CPT (p = 0.492), LNB (p = 0.149), or NYU Paragraph Recall Task (p = 0.803) (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our sample was on average 41.5 years old at surgical menopause, much younger than the average age at natural menopause.

    “Our sample was on average 41.5 years old at surgical menopause, much younger than the average age at natural menopause.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The pharmacy team were the only personnel unblinded to assignment; study investigators, clinical research coordinators, and participants were blind to group assignment until participants completed all study procedures.

    “The pharmacy team were the only personnel unblinded to assignment and dispensed medication according to the randomization table in identical capsules for LDX and placebo. Study investigators, clinical research coordinators, and participants were blind to group assignment until participants completed all study procedures.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Analyses included all available data regardless of medication adherence or study completion in an intent-to-treat framework.

    “Analyses were performed in R version 4.2.1 and included all available data regardless of medication adherence or study completion in an intent-to-treat framework, without adjustment for multiple comparisons.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study was a double-blind, placebo-controlled, randomized crossover trial.

    “The study timeline of this double-blind, placebo-controlled, randomized crossover trial is presented in Fig. 1.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The trial was registered with clinical trial registration number NCT03187353.

    “The registration number of this clinical trial is NCT03187353.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Analyses were performed without adjustment for multiple comparisons.

    “Analyses were performed in R version 4.2.1 and included all available data regardless of medication adherence or study completion in an intent-to-treat framework, without adjustment for multiple comparisons.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    A priori power calculations were conducted assuming 2-sided type I error of 5% and 80% power; a sample size of 52 completers was chosen to provide 80% power to detect an effect size of 0.3 SD based on within-subject change.

    “A priori power calculations were conducted assuming 2-sided, type I error of 5%, and 80% power for a within-participant change between trial baseline and trial endpoint in total BADDS score for LDX versus placebo. A sample size of 52 completers was chosen because it would provide 80% power to detect an effect size of 0.3 SD based on within-subject change (i.e., a 17% greater reduction in total BAD”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Randomization was conducted by the University of Pennsylvania Investigational Drug Service pharmacy using www.randomizer.org to create a randomization table based on 100 subjects and randomized in blocks of 4.

    “The University of Pennsylvania Investigational Drug Service (IDS) pharmacy conducted randomization using www.randomizer.org to create the randomization table based on 100 subjects and randomized in blocks of 4.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Sixty-nine participants were randomized; 33 received placebo first and 36 received LDX first.

    “Sixty-nine participants were randomized; 33 participants received placebo first and 36 participants received LDX first.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Of the initial 69, 12 participants withdrew, were withdrawn, or were lost to follow-up; 57 completed the study.

    “Of the initial 69, a total of 12 participants withdrew, were withdrawn, or were lost to follow-up. Fifty-seven participants completed the study: 28 participants received placebo first and LDX second; 29 participants received LDX first and placebo second (Fig. S1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The primary outcome was self-reported executive functioning difficulties as measured with the BADDS.

    “The primary outcome was self-reported executive functioning difficulties as measured with the BADDS [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Brown TE, Brown Attention-Deficit Disorder Scales for Adolescents and Adults, The Psychological Corporation, 1996.

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Among those without contraindications, hormone therapy following RRSO is recommended.

    “Among those without contraindications, hormone therapy (HT) following RRSO is recommended [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Faubion SS, Crandall CJ, Davis L,, The 2022 hormone therapy position statement of the North American Menopause Society, Menopause 29 (7) (2022) 767– 794, 10.1097/GME.0000000000002028. 35797481 source

  • May combine two claims.

    Interpretationown data

    LDX's full effects on self-reported executive functioning were relatively rapid, delivering benefits by week 3 at up to 40 mg/day with sustained, but not additional, improvements through week 6.

    “LDX’s full effects on self-reported executive functioning were relatively rapid, delivering benefits by week 3 at up to 40 mg/day with sustained, but not additional, improvements through week 6.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The study used a double-blind, placebo-controlled, randomized controlled crossover trial design, including a minimum 2-week washout between trials, allowing women to serve as their own controls.

    “Strengths of this work include a double-blind, placebo-controlled, randomized controlled crossover trial design, including a minimum 2-week washout between trials, allowing women to serve as their own controls.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Most participants remained at 40 mg/day at two weeks (93.4% for placebo; 93.8% for LDX) per protocol.

    “Most participants remained at 40 mg/day (93.4% for placebo; 93.8% for LDX)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Our observation that, relative to placebo, LDX significantly improved working memory performance on the LNB, but not visual attention and vigilance on the CPT or verbal recall on the NYU Paragraph Recall Task, aligns with mechanism-based research of this psychostimulant and the brain regions it is hypothesized to impact.

    “Our observation that, relative to placebo, LDX significantly improved working memory performance on the LNB, but not visual attention and vigilance on the CPT or verbal recall on the NYU Paragraph Recall Task, aligns with mechanism-based research of this psychostimulant and the brain regions it is hypothesized to impact.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Most participants remained at 60 mg/day at four weeks (98.3% for placebo; 75.4% for LDX) per protocol.

    “and 60 mg/day (98.3% for placebo; 75.4% for LDX) at two and four weeks, respectively, per protocol.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Most participants were taking 60 mg/day at trial endpoints (81.7% for placebo; 84.2% for LDX).

    “Most participants were taking 60 mg/day at trial endpoints (81.7% for placebo; 84.2% for LDX) (Table S9).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    While performance on neurocognitive tests can lack ecological validity, they can provide valuable predictions of clinical diagnoses and problems in daily life and overcome participant bias in self-report measurements.

    “While performance on neurocognitive tests can lack ecological validity [40], they can provide valuable predictions of clinical diagnoses and problems in daily life [41] and overcome participant bias in self-report measurements.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Howieson D, Current limitations of neuropsychological tests and assessment procedures, Clin. Neuropsychol. 33 (2) (2019) 200– 208, 10.1080/13854046.2018.1552762. 30608020 source
    • cites [41] Donders J, The incremental value of neuropsychological assessment: a critical review, Clin. Neuropsychol. 34 (1) (2020) 56– 87, 10.1080/13854046.2019.1575471. 31014166 source

  • May combine two claims.

    Interpretationreasoning

    The NYU Paragraph Recall Task relies more heavily on intact hippocampal function than prefrontal cortical functioning and thus it is unsurprising that performance improvements on this verbal test were similar between trials.

    “The NYU Paragraph Recall Task relies more heavily on intact hippocampal function than prefrontal cortical functioning and thus it is unsurprising that performance improvements on this verbal test were similar between trials.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Reviews suggest that the positive effects of stimulant medication for ADHD experienced during randomized controlled trials relative to placebo were maintained during open-label follow-up periods in extension studies.

    “Reviews suggest that the positive effects of stimulant medication for ADHD experienced during randomized controlled trials relative to placebo were maintained during open-label follow-up periods in extension studies [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Fredriksen M, Halmøy A, Faraone SV, Haavik J, Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies, Eur. Neuropsychopharmacol. (2013) 508– 527, 10.1016/j.euroneuro.2012.07.016. 22917983 source

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

    Interpretationreasoning

    We cannot assume that the prevalence of post-RRSO executive functioning difficulties nor the treatment effects of LDX would be equivalent in a population of women with relatively less privilege.

    “we cannot assume that the prevalence of post-RRSO executive functioning difficulties nor the treatment effects of LDX would be equivalent in a population of women with relatively less privilege.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    BADDS scores predict clinical diagnosis of ADHD and multiple ADHD medication trials use the BADDS to assess symptom severity and improvement.

    “BADDS scores predict clinical diagnosis of ADHD [36] and multiple ADHD medication trials use the BADDS to assess symptom severity and improvement [16,37–39].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [36] Sandra Kooij JJ, Marije Boonstra A, Swinkels SHN, Bekker EM, De Noord I, Buitelaar JK, Reliability, validity, and utility of instruments for self-report and informant report concerning symptoms of ADHD in adult patients, J. Atten. Disord. 11 (4) (2008) 445– 458, 10.1177/1087054707299367. 18083961 source
    • cites [16] Brown TE, Brams M, Gao J, Gasior M, Childress A, Open-label administration of lisdexamfetamine dimesylate improves executive function impairments and symptoms of attention-deficit/hyperactivity disorder in adults, Postgrad. Med. 122 (5) (2010) 7– 17, 10.3810/pgm.2010.09.2196. 20861583 source
    • cites [37] Brown RT, Perrin JM, Measuring outcomes in attention-deficit/hyperactivity disorder, J. Pediatr. Psychol. 32 (6) (2007) 627– 630, 10.1093/jpepsy/jsm001. 17535818 source
    • cites [38] Brown TE, Landgraf JM, Improvements in executive function correlate with enhanced performance and functioning and health-related quality of life: evidence from 2 large, double-blind, randomized, placebo-controlled trials in ADHD, Postgrad. Med. 122 (5) (2010) 42– 51, 10.3810/pgm.2010.09.2200. 20861587 source
    • cites [39] Brown TE, Brams M, Gasior M,, Clinical utility of ADHD symptom thresholds to assess normalization of executive function with lisdexamfetamine dimesylate treatment in adults, Curr. Med. Res. Opin. 27 (Suppl. 2) (2011) 23– 33, 10.1185/03007995.2011.605441. 21973229 source

  • May combine two claims.

    Study design and conductown data

    Although rates of completion between LDX and placebo groups were similar, there were significantly more side effects reported in the LDX condition, which may have unblinded them to treatment condition and may have biased the self-report of executive functioning.

    “Although rates of completion between LDX and placebo groups were similar, there were significantly more side effects reported in the LDX condition, which may have unblinded them to treatment condition and may have biased the self-report of executive functioning.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    While the CPT taps into sustained attention, a domain of executive function dependent on an intact prefrontal cortex, there was a ceiling effect; the task may not have been sufficiently challenging for this educated sample to demonstrate greater improvement with LDX versus placebo.

    “While the CPT taps into sustained attention, a domain of executive function dependent on an intact prefrontal cortex [30], there was a ceiling effect; the task may not have been sufficiently challenging for this educated sample to demonstrate greater improvement with LDX versus placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Rezai K, Andreasen NC, Alliger R, Cohen G, Swayze V, O’Leary DS, The neuropsychology of the prefrontal cortex, Arch. Neurol. 50 (6) (1993) 636– 642. 8503801 source

  • May combine two claims.

    Study design and conductown data

    We controlled for chemotherapy history in exploratory analyses; chemotherapy history did not change the significance of our findings.

    “We controlled for chemotherapy history in exploratory analyses; chemotherapy history did not change the significance of our findings.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Participants could be using traditional postmenopause hormone therapy, a selective estrogen receptor modulator, or an aromatase inhibitor in this study, though the study was not designed to address the impact of these drugs on cognition or response to LDX specifically.

    “Participants could be using traditional postmenopause hormone therapy, a selective estrogen receptor modulator, or an aromatase inhibitor in this study, though the study was not designed to address the impact of these drugs on cognition or response to LDX specifically.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    We included subjective and objective measures of executive functioning, offering strengths and balancing limitations of both measurement types.

    “We included subjective and objective measures of executive functioning, offering strengths and balancing limitations of both measurement types.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    Our findings indicate that LDX could be considered a treatment option for post-RRSO cognitive complaints.

    “Our findings indicate that LDX could be considered a treatment option for post-RRSO cognitive complaints.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HT is often contraindicated or not used in this population and is otherwise partially effective; HT has not been studied specifically for new-onset executive function difficulties in peri- and early postmenopausal women.
    • Rests on an assumption: Prior to this work, no alternative treatment options to HT existed for post-RRSO cognitive concerns.
42 of 42

  • The paper relies on this without support.

    LDX is FDA approved for the treatment of ADHD.

    “The prodrug and psychostimulant lisdexamfetamine (LDX; Vyvanse®) is FDA approved for the treatment of attention deficit hyperactivity disorder (ADHD), the prototypical disorder characterized by executive function impairments.”

  • The paper relies on this without support.

    ADHD is the prototypical disorder characterized by executive function impairments.

    “The prodrug and psychostimulant lisdexamfetamine (LDX; Vyvanse®) is FDA approved for the treatment of attention deficit hyperactivity disorder (ADHD), the prototypical disorder characterized by executive function impairments.”

  • The paper relies on this without support.

    A minimum 2-week washout is sufficient to eliminate carryover effects between LDX and placebo trials.

    “After a minimum 2-week washout, participants were crossed over to the other drug treatment and the trial protocol was repeated.”

  • The paper relies on this without support.

    The trial sample is representative of women experiencing cognitive difficulties post-RRSO.

    “Lisdexamfetamine improved both subjective and objective measures of attention and working memory and could offer women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy an alternative therapeutic option.”

  • The paper relies on this without support.

    This is the first study to examine the impact of a psychostimulant on new-onset executive function difficulties following RRSO.

    “This is the first study to examine the impact of a psychostimulant on new-onset executive function difficulties following RRSO.”

  • The paper relies on this without support.

    HT is often contraindicated or not used in this population and is otherwise partially effective; HT has not been studied specifically for new-onset executive function difficulties in peri- and early postmenopausal women.

    “This is important because HT is often contraindicated or not used in this population and is otherwise partially effective; furthermore, HT has not been studied specifically for new-onset executive function difficulties in peri- and early postmenopausal women.”

  • The paper relies on this without support.

    Prior to this work, no alternative treatment options to HT existed for post-RRSO cognitive concerns.

    “To our knowledge, prior to this work, no alternative treatment options to HT existed for post-RRSO cognitive concerns.”
7 of 7

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Placebo responder percentage does not match its count

    Major

    The reported 32 responders among 59 placebo participants is 54.2%, not 45.8%. This misstates the placebo response rate used in the treatment comparison.

    Reported 45.8 · recomputed 54.237288

1 of 1

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Authors
Metcalf, C. A., Page, C. E., Stocker, B. O. S., Johnson, R. L., Duffy, K. A., Sammel, M. D., Loughead, J., & Epperson, C. N.
Affiliations
  • University of Colorado Anschutz (US)
  • University of Pennsylvania (US)
  • Colorado School of Public Health (US)
Corresponding author
Epperson, C. Neill
ORCID
Venue
Gynecologic Oncology
Publisher
Elsevier BV
Published
2024-11
Volume
190
Pages
62-69
ISSN
0090-8258 (ISSN-L)
DOI
10.1016/j.ygyno.2024.07.689
PMC
PMC11702344
OpenAlex
W4401565600
Cited by
7
References
40
Citations by year
2026: 3 · 2025: 3 · 2024: 1
FWCI
1.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Gynecologic Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
National Institutes of Health (R01 CA215587)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Keywords
lisdexamfetamine, risk-reducing salpingo-oophorectomy, executive function, attention, working memory, psychostimulants, breast cancer prevention, cognitive side effects
MeSH terms
Lisdexamfetamine Dimesylate, Salpingo-oophorectomy, Adult, Central Nervous System Stimulants, Double-Blind Method, Female, Humans, Middle Aged, Ovarian Neoplasms, Cross-Over Studies, Executive Function

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 2026-10-16.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.

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.

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