Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties
Open accessAbstract
Many women with no history of executive dysfunction report difficulties in this domain during the menopause transition. Lisdexamfetamine (LDX) has been suggested to be a safe and effective treatment option for these women. However, the mechanism by which LDX improves executive functioning in these women is not known. Here we investigated the effects of LDX on brain activation and neurochemistry, hypothesizing that LDX would be associated with increased activation and decreased glutamate in executive regions. Fourteen women underwent multimodal neuroimaging at 7T at three time points in this baseline-corrected, double-blind, placebo-controlled, crossover study. Effects of LDX on symptom severity, blood-oxygen-level-dependent (BOLD) signal, and dorsolateral prefrontal cortex (DLPFC) glutamate+glutamine (Glx) were measured using a clinician-administered questionnaire, fMRI during performance of a fractal n-back task, and 1 H-MRS, respectively. The effect of treatment (LDX minus baseline vs placebo minus baseline) on these behavioral and neural markers of executive function was examined using repeated measures mixed effects models. LDX treatment was associated with decreased symptom severity, increased activation in the insula and DLPFC, and decreased DLPFC Glx. In addition, the magnitude of LDX-induced improvement in symptom severity predicted both direction and magnitude of LDX-induced change in insular and DLPFC activation. Moreover, symptom severity was positively correlated with Glx concentration in the left DLPFC at baseline. These findings provide novel evidence that the neural mechanisms by which LDX acts to improve self-reported executive functioning in healthy menopausal women with midlife onset of executive difficulties include modulation of insular and DLPFC recruitment as well as decrease in DLPFC Glx concentration.
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During periods of low oestrogen, increased ADHD symptoms and decreased response to psychostimulant medication have been described.
“Additionally, during periods of low oestrogen, increased ADHD symptoms [30,41,91,92] and decreased response to psychostimulant medication [25,42,93,94,95] have been described.”
From A Female-Specific Treatment Group for ADHD—Description of the Programme and Qualitative Analysis of First Experiences (2024) · cites this paper as [91]
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].”
From Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine (2024) · cites this paper as [14]
Mechanism-based research among menopausal women suggests that LDX may impact executive functioning through modifying insular and dorsal lateral prefrontal cortex recruitment and decreasing glutamate levels in the dorsal lateral prefrontal cortex.
“Mechanism-based research among menopausal women suggests that LDX may impact executive functioning through modifying insular and dorsal lateral prefrontal cortex recruitment and decreasing glutamate levels in the dorsal lateral prefrontal cortex [14].”
From Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine (2024) · cites this paper as [14]
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Self-citation
- Authors
- Shanmugan, S., Loughead, J., Nanga, R. P. R., Elliott, M., Hariharan, H., Appleby, D., Kim, D., Ruparel, K., Reddy, R., Brown, T. E., & Epperson, C. N.
- Affiliations
- University of Pennsylvania (US)
- Yale University (US)
- Corresponding author
- Epperson, C Neill
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2016-08-23
- Volume
- 42
- Issue
- 2
- Pages
- 437-445
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5399233
- OpenAlex
- W2507664632
- Cited by
- 33
- References
- 37
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 3
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shire
- National Institute of Biomedical Imaging and Bioengineering (P41EB015893)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- lisdexamfetamine, menopause, executive function, executive dysfunction, menopausal women, dorsolateral prefrontal cortex, insula, glutamate, glutamine, brain activation, neurochemistry, symptom severity
- MeSH terms
- Lisdexamfetamine Dimesylate, Central Nervous System Stimulants, Double-Blind Method, Female, Glutamine, Humans, Memory, Short-Term, Menopause, Middle Aged, Prefrontal Cortex, Cross-Over Studies, Glutamic Acid, Executive Function
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