title: Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties.
abstract: 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, and1H-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.
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.|Penn Center for Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shanmugan
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Loughead
authors.affiliation: Department of Radiology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ravi Prakash Reddy
authors.initials: RP
authors.lastname: Nanga
authors.affiliation: Department of Radiology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Elliott
authors.affiliation: Department of Radiology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hari
authors.identifier: 0000-0002-7032-6968
authors.initials: H
authors.lastname: Hariharan
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Appleby
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.|Penn Center for Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.affiliation: Department of Radiology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Reddy
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Brown
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.|Penn Center for Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.|Department of Obstetrics and Gynecology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C Neill
authors.initials: CN
authors.lastname: Epperson
mesh_terms: D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D056344:Executive Function / Q000187:drug effects* / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate / Q000008:administration & dosage*; D008570:Memory, Short-Term / Q000187:drug effects; D008593:Menopause / Q000523:psychology*; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D005973:Glutamine; D018698:Glutamic Acid; D000069478:Lisdexamfetamine Dimesylate