12 October, 2015: 

Some cognitive decline, particularly in the domains of executive functions, is common among menopausal women. A new study has examined the effect of the psychostimulant lisdexamfetamine (LDX) on subjective and objective cognitive function among menopausal women who report new-onset executive function complaints [1]. LDX is a very popular medication indicated for the treatment of attention deficit hyperactive disorder (ADHD). Thirty-two healthy perimenopausal and early postmenopausal women experiencing mid-life-onset executive function difficulties, as measured using the Brown Attention Deficit Disorder Scale (BADDS), were administered LDX 40–60 mg/day for 4 weeks in this double-blind, placebo-controlled, cross-over study. Diagnosis of lifetime ADHD was exclusionary. BADDS total and subscale scores and performance on verbal memory and working memory tasks were outcomes of interest. Analyses revealed a significant effect of LDX treatment over placebo for total BADDS scores (p= 0.0001) and for four out of the five BADDS subscales (allp< 0.004). LDX treatment also resulted in significant improvement in delayed paragraph recall (p= 0.018), but there was no significant effect of treatment on other cognitive measures. Systolic blood pressure (p= 0.017) and heart rate increased significantly (p= 0.006) when women were on LDX but remained, on average, within the normal range. Treatment was well tolerated and improved the subjective measures of executive function as well as objective measures of delayed verbal recall in this sample of healthy menopausal women. The above study results raise several questions: (1) could some of the classical adult ADHD symptoms be related to reciprocal menopausal complaints? (2) Should we use psychostimulants as a therapeutic mode for certain menopausal ill outcomes, especially within the cognitive domains?

Comment

ADHD is a neurobehavioral disease characterized by excessive hyperactivity, inattention, and impulsiveness; it is wrongly considered to occur in children and adolescents and to wane or disappear in later years [2,3]. This relatively newly recognized cluster of symptoms is now included in the DSM list of psychiatric illnesses, and its pathophysiology, clinical features, outcomes, co-morbidities and treatment have been constantly updated and better understood. In fact, originally thought to be a childhood disorder, its clinical presentation may change with age and become more conspicuous, yet it may actually remain throughout life. Estimates of ADHD prevalence are around 5–6% for children and adolescents. It is believed that 2–5% of the adult population have ADHD manifestations and that about one-half are diagnosed already in early childhood and continue to have some of its features as adults [4,5]. While addressing adult ADHD, most of the studies and reviews bring data on people younger than 30 years old. An exception was the study of Faraone and colleagues, which included a group with late-onset ADHD, and the oldest age recorded was 55 years [6]. Shaw's extensive review included an adult group with the highest age of 84 years, but no further age details were disclosed [7]. The authors concluded that their analysis supports the premise that, without treatment, people with ADHD often experience poorer long-term outcomes and that treatment may improve the long-term outcomes of ADHD for some individuals, but not necessarily to the degree of healthy controls. To note that ADHD prevalence and rate of symptom persistence over time seem to be highly affected by methodological characteristics of the studies. Typical features of adult ADHD include constant mental activity, feelings of restlessness and difficulty engaging in sedentary activities, boredom, inability to concentrate, disorganization, mood lability and sensitivity to stress [4]. Additionally, tasks are not completed, problem-solving is lacking in strategy and time management is particularly poor. Impulsivity continues and leads to problems in teamwork, abrupt initiation and termination of relationships, and a tendency to make rapid and facile decisions without full analysis of the situation [8]. As a matter of fact, the wide variability of potential features of ADHD may actually weaken its special distinction from other cognitive and psychiatric disorders which share similar characteristics.

There is a gender difference in the incidence and expression of ADHD [9-11]. Boys outnumber girls at least 2 : 1 in preponderance, and the co-morbidity profile show that females tend to have more physiological components of anxiety. Some therapists claim that ADHD symptomatology ameliorates during pregnancy. Genetic and hormonal factors were suggested as potential causes of these gender variances, and the intriguing question is whether the change in ADHD symptomatology in adults has any relevance to these gender discrepancies. Needless to say, the first assumption that comes into mind while investigating a situation that occurs much more, or much less frequently in women, as compared to men, is that there could be an association with sex hormones. It is well established that estrogen and progesterone have various brain effects which are linked to affect, emotions, behavior and cognitive function. Fluctuations of sex hormone levels during the menstrual cycle clearly impact the above parameters in many women, whereas the menopause-related estrogen deficiency state creates another expression of such interactions. ADHD, with its male preponderance and neurobehavioral characteristics, which resemble those related to the impact of changes in the sex hormone milieu in women, raises intriguing questions that need to be addressed. Sex hormones have the ability to regulate intracellular signaling systems that are thought to be abnormal also in ADHD. Could the interplay between estrogen and brain dopamine or serotonin or other neurotransmitters (glutamine, acetylcholine) be among the underlying mechanisms in ADHD?

Interestingly, as found in a Canadian survey, there were more midlife females then males who self- reported a diagnosis of ADHD sometime during their life [12]. Assessment of mental disorders by standard instruments showed that the ADHD group had a higher prevalence of psychiatric diagnoses then the control group, whereas women had more lifetime or current depressive and anxiety disorders than men. The occurrence of ADHD in midlife women brings forward the question whether menopauseper seor the related estrogen deficiency has any potential effect or interaction with ADHD symptomatology. Favorable outcomes of off-label therapies indicated for ADHD tested in menopausal women with cognitive impairments provide a possible indirect link for such an assumption [1,13]. Thus LDX improved the domains of executive function and delayed verbal recall [1], whereas atomoxetine given to perimenopausal and postmenopausal women presenting with midlife-onset subjective cognitive difficulties resulted in improvement in memory and attention/concentration [13]. One may argue and should be cautious with interpretation of such data, since ADHD therapies are actually based on psychostimulants that have certain brain effects at any age, regardless of menopause. Nevertheless, the findings suggest that some women report a syndrome of cognitive difficulties emerging in midlife that bear strong resemblance to cognitive impairments commonly reported by adults with ADHD. Perhaps a link to estrogen might be the missing piece in that puzzle. The effects of sex hormones on brain function and cognitive performance are very well documented, and so are the outcomes of the menopause-related hormone deficiency in these respects [11]. It seems logical that the hormonal milieu, whether derived from endogenic sources or from medications, is involved and interacts with neurotransmitters and various brain pathways, and can lead to cognitive, emotional and mood changes which resemble those found in adult female ADHD patients. However, despite favorable effects on certain menopausal symptoms of medications identified with ADHD treatment, relevant data are still insufficient for establishing a clear link. Perhaps the right phrasing for future research should be: can cognitive complaints in midlife or menopausal women be treated successfully with psychostimulants?

I am grateful to Pauline Maki (Department of Psychiatry, University of Illinois at Chicago, USA) and Michael Craig (Human Cognitive Neuroscience, Department of Psychology, The University of Edinburgh, UK), for their valuable comments.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

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