Sex and gender differences in the treatment of Alzheimer’s disease: A systematic review of randomized controlled trials

Canevelli, Marco; Quarata, Federica; Remiddi, Francesca; Lucchini, Flaminia; Lacorte, Eleonora; Vanacore, Nicola; Bruno, Giuseppe; Cesari, Matteo

doi:10.1016/j.phrs.2016.11.035

Cited by 71 publications

(51 citation statements)

References 31 publications

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“…Clinical and pre-clinical studies demonstrate conflicting evidence on sex differences in response to anticholinesterase medications, a widely used therapy for AD. Some studies have reported that females responded better than males in clinical [102] and in AD models [103], whilst recent meta-analysis study have no significant sex differences [104]. Overall, women show a greater rate of prevalence and incidence, increased cognitive decline and greater rate of neuropathological decline in AD compared to men.…”

Section: Female-biased Brain Disordersmentioning

confidence: 99%

Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

et al. 2018

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Males and females sometimes significantly differ in their propensity to develop neurological disorders. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson’s disease (PD), attention-deficit hyperactivity disorder (ADHD) and autism. Despite this, biological sex is rarely considered when making treatment decisions in neurological disorders. A better understanding of the molecular mechanism(s) underlying sex differences in the healthy and diseased brain will help to devise diagnostic and therapeutic strategies optimal for each sex. Thus, the aim of this review is to discuss the available evidence on sex differences in neuropsychiatric and neurodegenerative disorders regarding prevalence, progression, symptoms and response to therapy. We also discuss the sex-related factors such as gonadal sex hormones and sex chromosome genes and how these might help to explain some of the clinically observed sex differences in these disorders. In particular, we highlight the emerging role of the Y-chromosome gene, SRY, in the male brain and its potential role as a male-specific risk factor for disorders such as PD, autism, and ADHD in many individuals.

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Section: Female-biased Brain Disordersmentioning

confidence: 99%

Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

et al. 2018

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“…Take, for example, the case of acetylcholinesterase inhibitors (AChEI), which have been prescribed for Alzheimer's disease for decades, so knowledge of sex differences in drug effects would be anticipated [191]. However, two recent reviews found that there is almost a complete lack of sex-specific reporting on AChEI drug trial data [191,193]. In fact, none of the trials assessing AChEI safety and tolerability in Alzheimer's patients reported findings of by sex [193].…”

Section: Future Research Directionsmentioning

confidence: 99%

“…However, two recent reviews found that there is almost a complete lack of sex-specific reporting on AChEI drug trial data [191,193]. In fact, none of the trials assessing AChEI safety and tolerability in Alzheimer's patients reported findings of by sex [193]. Clearly, more efforts to compare drug trial effects by sex are needed to decrease harmful side-effects and reduce research value lost [194].…”

Section: Future Research Directionsmentioning

confidence: 99%

Sex differences in stress reactivity in arousal and attention systems

Bangasser

Eck

Sanchez

2018

Neuropsychopharmacol

130

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Women are more likely than men to suffer from psychiatric disorders with hyperarousal symptoms, including posttraumatic stress disorder (PTSD) and major depression. In contrast, women are less likely than men to be diagnosed with schizophrenia and attention deficit hyperactivity disorder (ADHD), which share attentional impairments as a feature. Stressful events exacerbate symptoms of the aforementioned disorders. Thus, researchers are examining whether sex differences in stress responses bias women and men towards different psychopathology. Here we review the preclinical literature suggesting that, compared to males, females are more vulnerable to stress-induced hyperarousal, while they are more resilient to stress-induced attention deficits. Specifically described are sex differences in receptors for the stress neuropeptide, corticotropin-releasing factor (CRF), that render the locus coeruleus arousal system of females more vulnerable to stress and less adaptable to CRF hypersecretion, a condition found in patients with PTSD and depression. Studies on the protective effects of ovarian hormones against CRF-induced deficits in sustained attention are also detailed. Importantly, we highlight how comparing males and females in preclinical studies can lead to the development of novel therapeutics to improve treatments for psychiatric disorders in both women and men.

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“…However, the authors remarked that “most available evidence was compromised by methodological limitations” precluding any deep inquiry about the impact of sex differences on efficacy and toxicity. Further cumulative evidence has matured in various fields (Klein et al, 2015) including neurosciences (Cahill, 2006, 2017), neurodegenerative diseases (Bove and Chitnis, 2013; Canevelli et al, 2017), medication use and treatment adherence (Chen et al, 2014; Manteuffel et al, 2014), incidence of DDI (Bowlin et al, 2013) as well as clinical and preclinical research (Franconi and Campesi, 2014a,b; Mazure, 2016; Segarra et al, 2016). This evidence has pushed forward more clearly the need to address potential sex-based differential clinical effects on male and female patients with the inclusion of covariate sex in the outcome analysis for the benefit of patients (Segarra et al, 2016; Cahill, 2017).…”

Section: Introductionmentioning

confidence: 99%

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

et al. 2017

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The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug–drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies.

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Sex and gender differences in the treatment of Alzheimer’s disease: A systematic review of randomized controlled trials

Cited by 71 publications

References 31 publications

Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

Sex differences in stress reactivity in arousal and attention systems

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

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