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This systematic review aimed to assess the types and effectiveness of interventions that sought to reduce anticholinergic burden (ACB) in people with dementia (PwD) in primary care.One trial registry and eight electronic databases were systematically searched to identify eligible English language studies from inception until December 2021. To be eligible for inclusion, studies had to be randomised controlled trials (RCTs) or non-randomised studies (NRS), including controlled before-and-after studies and interrupted time-series studies, of interventions to reduce ACB in PwD aged ≥65 years (either community-dwelling or care home residents). All outcomes were to be considered. Quality was to be assessed using the Cochrane Risk of Bias tool for RCTs and ROBINS-I tool for NRS. If data could not be pooled for meta-analysis, a narrative synthesis was to be conducted.In total, 1880 records were found, with 1594 records remaining after removal of duplicates. Following title/abstract screening, 13 full-text articles were assessed for eligibility. None of these studies met the inclusion criteria for this review. Reasons for exclusion were incorrect study design, ineligible study population, lack of focus on reducing ACB, and studies conducted outside the primary care setting.This 'empty' systematic review highlights the lack of interventions to reduce ACB in PwD within primary care, despite this being highlighted as a priority area for research in recent clinical guidance. Future research should focus on development and testing of interventions to reduce ACB in this patient population through high-quality clinical trials.

Objective: Anticholinergic burden refers to the cumulative effect of medications which contain anticholinergic properties. We assessed how anticholinergic burden and different types of anticholinergic medications influence mortality rates among people with dementia in Northern Ireland. Our secondary aim was to determine what demographic characteristics predict the anticholinergic burden of people with dementia. Methods: Data were extracted from the Enhanced Prescribing database for 25,418 people who were prescribed at least one dementia management medication between 2010 and 2016.Information was also extracted on the number of times each available anticholinergic drug was prescribed between 2010 and 2016, allowing the calculation of an overall anticholinergic burden. Cox proportional hazard models were used to determine how anticholinergic burden influenced mortality whilst multilevel model regression determined what demographic characteristics influence overall anticholinergic burden. Results: Of the 25,418 people with dementia, only 15% (n ¼ 3880) had no anticholinergic burden. Diazepam (42%) and risperidone (18%) were the two most commonly prescribed drugs. Unadjusted Cox proportional hazard models indicated that higher anticholinergic burden was associated with significantly higher mortality rates in comparison to people with dementia who had no anticholinergic burden (HR ¼ 1.59: 95% CI ¼ 1.07-2.36). In particular, urological (HR ¼ 1.20: 95%CI ¼ 1.05-1.38) and respiratory (HR ¼ 1.17: 95% CI ¼ 1.08-1.27) drugs significantly increased mortality rates. People with dementia living in areas with low levels of deprivation had significantly lower anticholinergic burden (HR=-.39: 95% CI=-.47:-30).Conclusions: Reducing anticholinergic burden is essential for people with dementia. Further research should address the unfavourable prognosis of people living with dementia in highly deprived areas.

Objective To explore the role of chronic inflammation in rheumatoid arthritis (RA) on cognition. Methods and analysis Six hundred sixty-one men and women aged ≥55 years who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for RA were recruited from three healthcare trusts in the United Kingdom (UK) between May 2018 and March 2020. Study participants took part in interviews which captured sociodemographic information, followed by an assessment of cognition. RA specific clinical characteristics were obtained from hospital medical records. Participants were cognitively assessed using the Montreal Cognitive Assessment (MoCA) and were classified as cognitively impaired if they scored ≤27/30 points. Linear regression analyses were conducted to identify which demographic and clinical variables were potential predictors of cognitive impairment. Results The average age of participants was 67.6 years and 67% (444/661) were women. 72% (458/634; 95% CI 0.69 to 0.76) of participants were classified as cognitively impaired (MoCA≤27). Greater cognitive impairment was associated with older age (p = .006), being male (p = .041) and higher disease activity score (DAS28) (with moderate (DAS28 > 3.1) (p = 0.008) and high (DAS28 > 5.1) (p = 0.008)) compared to those in remission (DAS28 ≤ 2.6). There was no association between MoCA score and education, disease duration, RF status, anti-cyclic citrullinated peptide (anti-CCP) status, RA medication type or use of glucocorticoids or non-steroidal anti-inflammatory drugs (p > 0.05). Conclusion This study suggests that cognitive impairment is highly prevalent in older adults with RA. This impairment appears to be associated with higher RA disease activity and supports the concept that chronic systemic inflammation might accelerate cognitive decline. This underlines the importance of controlling the inflammatory response.

Introduction:The increasing number of people with dementia (PwD) is a significant health and financial challenge for countries. PwD often transition to a care home. This study explored factors predicting transition to care homes for PwD and the place and causes of death.Methods:Data about dementia medication, care home transitions, demographic characteristics, deaths, and hospital admissions were extracted from national databases from 2010 to 2016.Results:PwD (n = 25,418) were identified through prescriptions of dementia medication, from which 11,930 transitioned to care homes. A logistic regression showed that increased age, female sex, living in less deprived and urban areas, and hospital admissions predicted this transition. PwD who transition to care homes are more likely to die there. The most common cause of death was dementia.Discussion:Certain demographic characteristics are significant predictors for care home transitions and they should be considered in the development of early community‐based care services to delay transitions. In the last decades, dementia has been reported more frequently in death certificates

Access to affordable, objective and scalable biomarkers of brain function is needed to transform the healthcare burden of neuropsychiatric and neurodegenerative disease. Electroencephalography (EEG) recordings, both resting and in combination with targeted cognitive tasks, have demonstrated utility in tracking disease state and therapy response in a range of conditions from schizophrenia to Alzheimer's disease. But conventional methods of recording this data involve burdensome clinic visits, and behavioural tasks that are not effective in frequent repeated use. This paper aims to evaluate the technical and human-factors feasibility of gathering large-scale EEG using novel technology in the home environment with healthy adult users. In a large field study, 89 healthy adults aged 40–79 years volunteered to use the system at home for 12 weeks, 5 times/week, for 30 min/session. A 16-channel, dry-sensor, portable wireless headset recorded EEG while users played gamified cognitive and passive tasks through a tablet application, including tests of decision making, executive function and memory. Data was uploaded to cloud servers and remotely monitored via web-based dashboards. Seventy-eight participants completed the study, and high levels of adherence were maintained throughout across all age groups, with mean compliance over the 12-week period of 82% (4.1 sessions per week). Reported ease of use was also high with mean System Usability Scale scores of 78.7. Behavioural response measures (reaction time and accuracy) and EEG components elicited by gamified stimuli (P300, ERN, Pe and changes in power spectral density) were extracted from the data collected in home, across a wide range of ages, including older adult participants. Findings replicated well-known patterns of age-related change and demonstrated the feasibility of using low-burden, large-scale, longitudinal EEG measurement in community-based cohorts. This technology enables clinically relevant data to be recorded outside the lab/clinic, from which metrics underlying cognitive ageing could be extracted, opening the door to potential new ways of developing digital cognitive biomarkers for disorders affecting the brain.

Background:Understanding factors associated with mortality after a dementia diagnosis can provide essential information to the person with dementia, their family, and caregivers. To date very little is known about the factors associated with mortality after a dementia diagnosis in Northern Ireland.Objective:To determine how demographic and other factors such as deprivation and comorbidity medications influence mortality rates after a dementia diagnosis in Northern Ireland and whether these factors are influenced through nursing home transitions.Methods:25,418 people prescribed anti-dementia medication were identified through the enhanced prescribing database between 2010 and 2016. The impact of covariates including age, gender, marital status, deprivation measure, urban/rural classification, and comorbidity medications were examined using cox proportional hazard models with hazard ratios (HR) and 95% confidence intervals.Results:Between 2010 and 2016, 12,129 deaths occurred, with 114 deaths/1,000 person years. Males had significantly higher mortality rates in comparison to females (HR = 1.28; 95% CI = 1.23–1.33); this was true regardless of whether the person with dementia transitioned to a nursing home. People prescribed anti-dementia drugs living with lower levels of deprivation had significantly lower mortality rates in comparison to people living with the highest levels of deprivation (HR = 0.93; 95% CI = 0.89–0.97). Diabetic (HR = 1.18; 95% CI = 1.07–1.29) and anti-arrhythmic (HR = 2.44; 95% CI = 1.01–5.91) medication in particular significantly influenced mortality.Conclusion:Male gender, higher comorbidity medications, and living in areas of higher deprivation significantly increased mortality rates for people prescribed anti-dementia drugs in our study population. When comorbidity medications were classified, only anti-arrhythmia and diabetic medications significantly increased mortality. Future research should continue to investigate factors which influence mortality after a dementia diagnosis.

Serum antioxidants may afford neuroprotection against Alzheimer's disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of α-carotene, β-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate β-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance.

This is a conference abstract from the Alzheimer's Association International Conference 2019 in Los Angeles, California from 14-18 July 2019.

IntroductionOxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). We investigated associations between serum levels of lipophilic antioxidants and AD.MethodsSerum concentrations of retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography from patients with AD (n = 251) and cognitively intact controls (n = 308) and assessed by regression analyses.ResultsSerum levels of α-tocopherol and all six carotenoids were significantly lower in patients with AD compared with cognitively intact controls (P < .001). In contrast, γ-tocopherol was significantly higher in the serum of patients with AD (odds ratio = 1.17 [confidence intervals: 1.05–1.31]).DiscussionOur findings implicate compromised serum antioxidant defenses in AD pathogenesis and differing biological roles for vitamin E isoforms. This highlights the need for improved understanding in the balanced upregulation of exogenous antioxidants related to dietary intake or supplement use in future nutritional intervention studies.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) are neuroimaging modalities typically used for evaluating brain changes in Alzheimer’s disease (AD). Due to their complementary nature, their combination can provide more accurate AD diagnosis or prognosis. In this work, we apply a multi-modal imaging machine-learning framework to enhance AD classification and prediction of diagnosis of subject-matched gray matter MRI and Pittsburgh compound B (PiB)-PET data related to 58 AD, 108 mild cognitive impairment (MCI) and 120 healthy elderly (HE) subjects from the Australian imaging, biomarkers and lifestyle (AIBL) dataset. Specifically, we combined a Dartel algorithm to enhance anatomical registration with multi-kernel learning (MKL) technique, yielding an average of >95% accuracy for three binary classification problems: AD-vs.-HE, MCI-vs.-HE and AD-vs.-MCI, a considerable improvement from individual modality approach. Consistent with t-contrasts, the MKL weight maps revealed known brain regions associated with AD, i.e., (para)hippocampus, posterior cingulate cortex and bilateral temporal gyrus. Importantly, MKL regression analysis provided excellent predictions of diagnosis of individuals by r2 = 0.86. In addition, we found significant correlations between the MKL classification and delayed memory recall scores with r2 = 0.62 (p < 0.01). Interestingly, outliers in the regression model for diagnosis were mainly converter samples with a higher likelihood of converting to the inclined diagnostic category. Overall, our work demonstrates the successful application of MKL with Dartel on combined neuromarkers from different neuroimaging modalities in the AIBL data. This lends further support in favor of machine learning approach in improving the diagnosis and risk prediction of AD.

This is a conference abstract from the Alzheimer's Association International Conference in Los Angeles, California from 14-18 July 2019.

A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer’s disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.

Objective There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers. Design A literature search was performed using PubMed up to September 2011 for reviews and primary research studies of neuroimaging (magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and amyloid imaging), CSF and blood-based (plasma, serum and platelet) biomarkers in AD and mild cognitive impairment. Citations within individual articles were examined to identify additional studies relevant to this review. Results Evidence of AD biomarker potential was available for imaging techniques reflecting amyloid burden and neurodegeneration. Several CSF measures are promising, including 42 amino acid β-amyloid peptide (Aβ42); total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting neurofibrillary tangle pathology. Studies of plasma Aβ have produced inferior diagnostic discrimination. Alternative plasma and platelet measures are described, which represent potential avenues for future research. Conclusions Several imaging and CSF markers demonstrate utility in predicting AD progression and determining aetiology. These require standardisation before forming core elements of diagnostic criteria. The enormous potential available for identifying a minimally-invasive, easily-accessible blood measure as an effective AD biomarker currently remains unfulfilled. Copyright © 2012 John Wiley & Sons, Ltd.

IntroductionMild cognitive impairment (MCI) has clinical value in its ability to predict later dementia. A better understanding of cognitive profiles can further help delineate who is most at risk of conversion to dementia. We aimed to (1) examine to what extent the usual MCI subtyping using core criteria corresponds to empirically defined clusters of patients (latent profile analysis [LPA] of continuous neuropsychological data) and (2) compare the two methods of subtyping memory clinic participants in their prediction of conversion to dementia.MethodsMemory clinic participants (MCI, n = 139) and age-matched controls (n = 98) were recruited. Participants had a full cognitive assessment, and results were grouped (1) according to traditional MCI subtypes and (2) using LPA. MCI participants were followed over approximately 2 years after their initial assessment to monitor for conversion to dementia.ResultsGroups were well matched for age and education. Controls performed significantly better than MCI participants on all cognitive measures. With the traditional analysis, most MCI participants were in the amnestic multidomain subgroup (46.8%) and this group was most at risk of conversion to dementia (63%). From the LPA, a three-profile solution fit the data best. Profile 3 was the largest group (40.3%), the most cognitively impaired, and most at risk of conversion to dementia (68% of the group).DiscussionLPA provides a useful adjunct in delineating MCI participants most at risk of conversion to dementia and adds confidence to standard categories of clinical inference.

Evidence accumulating from biological and epidemiological studies suggests that high levels of serum cholesterol may promote the pathological processes that lead to Alzheimer's disease (AD). Lowering cholesterol in experimental animal models slows the expression of Alzheimer's pathology. These findings raise the possibility that treating humans with cholesterol lowering medications might reduce the risk of developing AD or help treat it. The statins (lovastatin, pravastatin, simvastatin, and others) are powerful cholesterol lowering agents of proven benefit in vascular disease. Several clinical studies comparing the occurrence of AD between users and non-users of statins suggested that risk of AD was substantially reduced among the users. However, because these studies were not randomized trials, they provided insufficient evidence to recommend statin therapy. Cochrane reviews are based on the best available information about healthcare interventions and they focus primarily on randomized controlled trials (RCTs). On the issue of prevention, two randomized trials have been carried out and neither showed any reduction in occurrence of AD in patients treated with statins compared to those given placebo. Statins cannot therefore be recommended for the prevention of AD. Regarding treatment of AD, the large RCTs which have assessed this outcome have not published their results. Initial analysis from the studies available indicate statins have no benefit on the outcome measure ADAS-Cog but have a significant beneficial effect on MMSE as an outcome. We need to await full results from the RCTs before we can be certain. In addition statins were not detrimental to cognition in either systematic review.

Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p < 0.001) and iron higher (10-16%; p < 0.001) in severe AD compared with controls. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation.

International audience; Objective: To compare performance of patients with mild-moderate Alzheimer's disease (AD) & Vascular Dementia (VaD) on tests of information processing and on specific tests of selective, divided and sustained attention. Method: Patients with AD (n=75) & VaD (n=46) were recruited from a memory clinic along with dementia-free participants(n=28). They underwent specific tests of attention from the Cognitive Drug Research (CDR) battery and pen and paper tests including Colour Trails A and B and Stroop. All patients had a CT brain scan which was independently scored for white matter change/ischaemia. Results: Attention was impaired in both the AD & VaD patients. VaD patients had more impaired choice reaction times and were less accurate on a vigilance test measuring sustained attention. Deficits in selective and divided attention occurred in both patient groups and showed the strongest correlations with MMSE scores. Conclusion: This study demonstrates problems with the attentional network in mild-moderate AD and VaD. We propose attention should be tested routinely in a memory clinic setting.

A healthy lifestyle may help maintain cognitive function and reduce the risk of developing dementia. This study employed a focus group approach in order to gain insight into opinions of mild cognitive impairment (MCI) patients, caregivers (CG) and health professionals (HP) regarding lifestyle and its relationship with cognition. The qualitative data were used to design, develop and pilot test educational material (EM) to help encourage lifestyle behaviour change.Data gathering phase: structured interviews were conducted with HP (n = 10), and focus groups with MCI patients (n = 24) and CG (n = 12). EM was developed and pilot tested with a new group of MCI patients (n = 21) and CG (n = 6).HP alluded to the lack of clinical trial evidence for a lifestyle and MCI risk link. Although they felt that lifestyle modifications should be recommended to MCI patients, they appeared hesitant in communicating this information and discussions were often patient-driven. MCI patients lacked awareness of the lifestyle cognition link. Participants preferred EM to be concise, eye-catching and in written format, with personal delivery of information favoured. Most pilot testers approved of the EM but were heterogeneous in terms of lifestyle, willingness to change and support needed to change.MCI patients need to be made more aware of the importance of lifestyle for cognition. EM such as those developed here, which are specifically tailored for this population would be valuable for HP who, currently, appear reticent in initiating lifestyle-related discussions. Following further evaluation, the EM could be used in health promotion activities targeting MCI patients.

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Psychotic symptoms occur in similar to 40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on > 1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 x 10(-7); 'AD+PvControls' P=1.11 x 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 x 10(-7)) and within VSNL1 (rs4038131, P=5.9 x 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized. Molecular Psychiatry (2012) 17, 1316-1327; doi: 10.1038/mp.2011.125; published online 18 October 2011

A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.