Many women entering the menopausal transition experience cognitive difficulties, which can significantly impact their quality of life and prove challenging to treat. These cognitive changes are often attributed to hormonal fluctuations, specifically declining estrogen levels. Surgical menopause, induced by risk-reducing salpingo-oophorectomy (RRSO), is associated with more severe cognitive impairments compared to natural menopause, with younger age at surgical menopause leading to worse cognitive outcomes.
While previous studies have indicated that estrogen replacement therapy may help to alleviate these cognitive complaints, many women may not be good candidates for or may chose not to pursue hormonal treatment. A recent study examined whether the psychostimulant lisdexamfetamine (LDX) improves subjective and objective measures of cognitive functioning in a group of women who had undergone salpingo-oophorectomy and reported new-onset executive functioning difficulties. (This procedure was undertaken as a means of reducing cancer risk in women genetically at risk for cancer.) Women with diagnoses of substance use disorder and ADHD were excluded from the study.
Study Design
In this randomized controlled crossover trial, 69 participants were assigned to 6-week trials of active medication (lisdexamfetamine) and placebo, separated by a minimum 2-week washout period. The lisdexamfetamine dosage was initiated at 20 mg and increased to 40 mg for the following two weeks. If tolerated, the dose was further increased to 60 mg for the remaining three weeks.
At trial baseline, midpoint, and endpoint, participants completed a self-report measure of executive functioning (Brown Attention Deficit Disorder Scale, BADDS). At study baseline and trial endpoint, participants also completed sustained attention, attention/working memory, and verbal learning/memory cognitive tasks.
Results
From trial baseline to endpoint, lisdexamfetamine – compared to placebo – significantly improved total scores on the self-report Brown Attention Deficit Disorder Scale. Participants in the LDX condition reported a 39.3% (SD = 26.7%) average reduction in overall executive functioning problems on the BADDS.
Treatment with lisdexamfetamine was associated with improvements in attention and working memory performance on objective cognitive tasks.
In placebo-controlled LDX trials for ADHD, participants were considered treatment “responders” if they had a ? 30% reduction in ADHD symptoms using a standardized scale. Using this definition, individuals in the LDX group were 3.64 times more likely than those in the placebo group to be classified as responders (95% CI: 2.01, 6.57; p < 0.001).
Significantly more participants in the LDX group experienced neurological/psychological side effects (e.g., headache, trouble sleeping or fatigue, nervousness; p = 0.001), decreased appetite (p < 0.001), and dry mouth (p < 0.001) compared to the placebo group. However, trial completion rates were similar, indicating that lisdexamfetamine was nonetheless well-tolerated.
Clinical Implications
In this study, the psychostimulant lisdexamfetamine improved both subjective and objective measures of attention and working memory, offering a potential therapeutic option for women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy. The improvements observed from LDX versus placebo in this trial were comparable to those observed in LDX trials of adults with ADHD.
While the results of this study are promising, further research is needed to examine the effectiveness of this intervention in women who experience natural menopause. The current study sample was on average 41.5 years old at surgical menopause, which is much younger than the average age at natural menopause. Future studies are needed to examine the effectiveness of LDX and other psychostimulants in the treatment of women who experience natural menopause. Additionally, long-term safety and efficacy of lisdexamfetamine in this population should be further investigated.
Ruta Nonacs, MD PhD
References
Metcalf CA, Page CE, Stocker BOS, Johnson RL, Duffy KA, Sammel MD, Loughead J, Epperson CN. Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine. Gynecol Oncol. 2024 Aug 14;190:62-69.
