Mortality risk associated with psychotropic medications frequently substituted for antipsychotics to manage behaviours that challenge in people with dementia: a systematic review

Mortality risk associated with psychotropic medications frequently substituted for antipsychotics to manage behaviours that challenge in people with dementia: a systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Mortality risk associated with psychotropic medications frequently substituted for antipsychotics to manage behaviours that challenge in people with dementia: a systematic review Grace Shepherd, Yolanda Lau, Claudia Cooper, Irene Petersen, Juan Carlos Bazo-Alvarez, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9539696/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: Antipsychotics, prescribed to manage behavioural and distress symptoms in dementia, are associated with increased mortality, so are often substituted with other medications. This review examines mortality risks associated with these alternatives. Method: We searched four electronic databases (January 2010 - October 2024), including randomised controlled trials, cohort and case-control studies involving people with dementia prescribed psychotropic medications (e.g., antidepressants, anxiolytics, mood stabilisers, sedatives, analgesics) other than antipsychotics. We assessed risk of bias using Cochrane Risk of Bias 2 and Newcastle-Ottawa Scale, and rated evidence certainty using GRADE criteria. Results: Thirty-six studies met inclusion criteria, most examining antidepressants (k=25). Only three were rated as being at low risk of bias. Low study quality and heterogeneity precluded meta-analyses. We found weak evidence of a trend in those prescribed antidepressants towards greater mortality risk in one high quality RCT, and lower risk in naturalistic cohort studies, relative to control conditions. Hypnotic, sedative or anxiolytic prescribing was not associated with greater all-cause mortality, relative to control conditions. Evidence for mood stabilisers/antiepileptics and opioids/analgesics was limited and inconsistent. Conclusions: Findings of a lack of clear association between prescribing and mortality should not be interpreted as evidence of safety. Future studies should examine impact of the drug types, dosages, treatment duration and adherence, to clarify potential within-class variation in mortality risk. Given the paucity of RCT evidence and practical challenges of powering trials for mortality, robust real-world studies are a priority. Pragmatic or registry-based randomised evaluations of mortality risks associated with treatment strategies may also be feasible. Figures Figure 1 Introduction In the United Kingdom (UK), an estimated 982,000 people have dementia. This is projected to exceed 2 million by 2050 (1), with societal dementia costs rising to £90 billion by 2040 (2). Three-quarters of people with dementia experience clinically significant behavioural or psychological symptoms of dementia (BPSD) such as agitation, depression, and anxiety (3). BPSD occur across all dementia subtypes (4), reduce quality of life (5) and increase care costs (6). Antipsychotics were a mainstay of BPSD management until concerns arose about their safety and effectiveness. A 2009 report estimated they contributed to 1,800 excess deaths annually, and increased cognitive decline and falls risk among people with dementia (7). National Institute for Health and Care Excellence guidelines recommend psychological approaches as first-line treatment for BPSD, because they are usually safer and more effective (8). Because of concerns about increased mortality, prescribers often substitute other drugs for antipsychotics. UK and Dutch primary care studies show that in people with dementia, antidepressant prescribing has increased as antipsychotic use has decreased since 2009 (9–11). This shift in prescribing was not matched by investment in access to psychological therapies. Older adults, especially those with dementia, struggle to access effective non-pharmacological therapies (12), and psychotropic use remains high. In an English care home study in 2014-15, 58% of residents with dementia were prescribed psychotropic medication, most commonly anxiolytics or hypnotics (13). While often perceived as safer, psychotropic drugs substituted for antipsychotics in people with dementia may also carry risks, including increased mortality (14–16). To our knowledge, no systematic review has explored these potential associated mortality risks. This study systematically reviewed studies published since the 2009 report, exploring mortality risks associated with psychotropic medication (other than antipsychotic drugs) used to manage BPSD in people with dementia. Methods Study design We preregistered this systematic review on PROSPERO (CRD42024602796) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Supplementary file A) Search strategy We searched four electronic databases, PsycINFO, Web of Science, PubMed and Scopus, from 1.1.2010 until 31.10.2024, adapting the search strategy for each database to include terms related to psychotropic medication, dementia, mortality and study design (Supplementary file B). We conducted forward and backward citation searches for eligible studies. No limits were placed on language. Study selection Using Covidence, two reviewers (from GS, HDK, CC, MY) independently screened titles and abstracts, then reviewed full text articles against eligibility criteria to identify relevant studies. Disagreements were resolved through discussion with a third independent reviewer (HDK or CC). We included randomised controlled trials (RCTs), cohort studies and case-control studies, quantitatively reporting mortality risks (compared to placebo or another drug) associated with psychotropic drugs, including antidepressants, anxiolytics, mood stabilisers, sedatives or analgesics, in a study population or separately analysed subgroup diagnosed with any dementia subtype. Studies focusing on antipsychotic medication (in line with our aim) or anti-dementia medications (prescribed primarily for cognition, rather than BPSD) were excluded. Data extraction We extracted data regarding study design, sample characteristics, psychotropic medication, follow up, and mortality risk estimates (risk ratio [RR] or hazard ratio [HR] where available, and where only cross-sectional data were available, odds ratio [OR]) associated with relevant medication and the covariates adjusted for in analyses. GS extracted all data, and MY independently extracted a 20% subset to ensure accuracy and consistency. We contacted authors of eligible studies to obtain missing data. Risk of bias and GRADE (Grade of Recommendations Assessment, Development and Evaluation) Two reviewers (from GS, CC, HDK, YL, MM) independently assessed risk of bias of included studies (Supplementary file C), resolving discrepancies through discussion with a third independent reviewer (HDK or CC). We used the Cochrane Risk of Bias 2 (RoB 2) for RCTs to evaluate internal validity. In line with tool procedures, each domain and overall risk of bias were rated as ‘low risk’, ‘some concerns’, or ‘high risk’(17). For observational cohort and case control studies, we used the Newcastle-Ottawa Scale. We defined good quality cohort studies as 3+ stars in the selection domain, 1+ stars in comparability domain and 2+ stars in the outcome/exposure domain (18). In the comparability domain, we considered both measured confounders and time-related biases. Measured confounders included age, gender, and confounding by indication. Time-related biases encompassed factors such as the definition of time zero and the handling of time-varying exposures, including immortal time bias. Two reviewers (YL, ES) independently determined the quality of evidence using GRADE, and discussed with co-authors to reach consensuses (19). For case control studies we rated studies scoring 7+ as low risk of bias, 5-6 as moderate and others as high risk of bias. Data synthesis and visualisation We used the metafor package (20) in R (version 4.4.1) for synthesis and visualisation (21). We intended to meta-analyse findings, but as study quality and heterogeneity precluded this, we used this package to generate forest plots to display data only and we summarised studies narratively. Original mortality risk estimates were grouped by drug class and we draw forest plots for RCTs (RRs), cohort studies (HRs), and case-control studies (ORs), only for descriptive purposes. When effect sizes were not reported, other available data were used for calculations. Results Search findings 34 out of 6,107 unique articles met eligibility criteria: three RCTs, 29 cohort studies, and two case-control studies (Figure 1). Study and population characteristics Sample sizes ranged from 76 to 67,072 (median: 3,374). Median follow-up duration was 12 months (range 3 to 96) . Studies included individuals with all-cause dementia (k=23), or specific dementia subtypes: Alzheimer’s (k=10), Parkinson’s disease and Lewy body dementia (k=1). Associations were reported with all-cause mortality (k=31); covid-related excess mortality (22), non-cancer (23) or hip fracture-related mortality (24). 22/29 (75.9%) cohort studies recruited prevalent users, Twenty-three studies (79.3%) implemented methods to address or mitigate immortal time bias, and two (6.9%) modelled drug use as a time-varying exposure. Study characteristics are presented in Tables 1-3. Psychotropic drug classes We reported mortality estimates in included studies, based on British National Formulary classifications (25): Antidepressants ( k =25) Hypnotics, anxiolytics, sedatives ( k =16) Opioids/ analgesics ( k =5) Mood stabilisers/ antiepileptics ( k =6) Mixed ( k =1) Supplementary file C details the medications studied. Thirteen studies fully specified drugs included in analysed categories, while 11 only reported broad categories (e.g. ‘benzodiazepines’, ‘antidepressants’). Other studies provided World Health Organisation-developed, anatomical therapeutic chemical classification (ATC) system codes (26) or specified British National Formulary sections for included drugs (27). Risk of bias Of the three RCTs, one was “low risk”, one had “some concerns”, and another was rated “high risk” of bias (Supplementary file D, Table 1). Of 29 cohort studies, all but one received a “high risk” rating, in almost every case due to low scores in the comparability domain (Supplementary file D Table 2). Of the two case-control studies, one was rated ‘low, and one ‘moderate risk’ (Supplementary file D, Table 3). Antidepressants RCTs Two double-blind RCTs conducted in England assessed the impact of mirtazapine on all-cause mortality (Supplementary file E, Figure 1). One study judged low risk of bias observed higher mortality in the mirtazapine relative to placebo arm (RR=7.0, 95%CI 0.9-55.9). However, the confidence interval was wide. (28). Another RCT found no difference in mortality between sertraline, mirtazapine or placebo (29). Cohort studies Thirteen studies reported HRs for the relationship between antidepressant use and all-cause mortality; these findings are summarised in Figure 2 in Supplementary file E. Overall, the evidence is mixed with some studies suggesting a protective, others a harmful effect. However, no clear pattern emerged. Three studies reported overlapping samples from Swedish national registry data collected since 2007; this dataset includes 90% of those diagnosed with dementia in Swedish memory services and 60% in primary care. The largest of these, which included patients with all-cause dementia (2007-13), found a lower mortality risk in memory clinic patients with dementia prescribed antidepressants compared to non-users, a year after dementia diagnosis (HR=0.92, 95%CI 0.86-0.99) (30). Two further studies reported increased mortality with antidepressant use in people with Parkinson’s disease dementia (HR=1.76, 95%CI 1.28-2.42), but not Lewy body dementia (HR=0.85, 95%CI 0.67-1.09) (31); and a forth study, using machine learning, that antidepressant use was a weak or non-significant predictor of mortality (32). Three additional studies reported that antidepressants were associated with a lower mortality risk, including a Swedish registry data study (33), USA Medicare data of long-stay nursing home residents (34), and people with depression and dementia prescribed higher antidepressant doses in a Taiwan National insurance database (35). Two studies with overlapping populations using linked UK electronic health records found that taking antidepressants (before or after, or only after dementia diagnosis) predicted higher mortality compared to non-users (36), with similar, non-significant findings in a second study (37). Five studies found no association between antidepressant prescribing and mortality. These involved: patients with dementia receiving antidementia medication in Greece (38); and Northern Ireland (27,39); and UK secondary mental healthcare patients with dementia (40); cohorts of community and nursing home residents with dementia in Finland and Sweden (41); and a Finnish community population with Alzheimer’s disease followed up after a hip fracture (24). Two studies did not report HR. One, a US study including patients from the Veterans Health Registries data, reported a lower mortality risk associated with antidepressant use compared with antipsychotics and valproic acid (42). The other, based on UK primary care and hospital records of those with dementia and sleep disturbance, found no increased mortality risk associated with low dose tricyclic antidepressants (43). Studies without a placebo arm In one of only two cohort studies judged to be at lower risk of bias, a Canadian nursing home study used medical records to compare outcomes between residents who were prescribed an antidepressant within the first 90 days of admission to those who were prescribed an atypical antipsychotic, and found a non-significant trend towards increased mortality in those prescribed antidepressants (23). By contrast, a second Canadian study compared adults with dementia living in long-term care with a new prescription of trazadone or atypical antipsychotics, finding a lower risk of mortality in people taking trazadone versus those taking atypical antipsychotics (44). A study using the German Pharmaco-epidemiological Research Database compared mortality risks of twelve different antidepressants with citalopram in patients with depression. Duloxetine, doxepin and trimipramine were associated with a lower risk, and amitriptyline a higher risk of mortality, compared with citalopram (45). Another study found no increase in mortality among patients with dementia in secondary psychiatric services taking antidepressants with higher versus lower cholinergic burden (46). Covid-related mortality One study compared an “exposure cohort” of people with dementia discharged from UK hospitals in 2020-22 after a covid illness requiring hospitalisation, to up to ten matched controls admitted with non-covid illnesses. The risk of mortality was higher among those admitted with covid (aHR=4.44, 95%CI 3.13–6.30); but did not find a greater mortality among those prescribed an antidepressant relative to those who were not (aHR=1.16, 95%CI 0.54-2.51) (22). Case control study In a study using Swedish health service data (n=10,341), cases had higher mortality odds (aOR = 1.14, [CI] 1.08-1.21) than age- and sex-matched controls (26). GRADE assessment We found weak evidence (downgraded due to inconsistency and imprecision) of a trend towards greater mortality risk in those prescribed antidepressants in RCTs, and lower risk in those prescribed antidepressants in cohort studies. Hypnotics, Anxiolytics, and Sedatives (k=16) Most drugs included in these categories were benzodiazepines; others were Z-drugs. There were 15 cohort and one case control study. Cohort studies Ten studies reported HR and are included in the forest plot (Supplementary file E, Figure 3). Of these, three reported an increased mortality risk. In a primary care national dataset from England, among people with dementia and sleep disturbance, those newly prescribed z-drugs had greater mortality risk than those not on sedative hypnotic medication (aHR=1.38, 95%CI 1.14-1.66) (47). Among people with Alzheimer’s disease from a London NHS trust, those taking hypnotics and anxiolytics medications prior to diagnosis had an increased mortality risk compared to non-users (37). A study involving the Finnish MEDALZ cohort of community-dwelling people with Alzheimer’s disease found a significant increase in risk of mortality over six months for users of benzodiazepines and Z-drugs (BZDRs), and, for benzodiazepines, compared to non-users (48). One study that included a subgroup of these participants reported similar findings (49). Seven studies reported no increased mortality risk. Specifically, no increased mortality risk associated with the prescription of hypnotic, sedative, or anxiolytic medications relative to non-use was observed among patients recruited from memory clinics in Australia (50), New Zealand (51) or Greece (38), or among people prescribed antidementia medication in Northern Ireland (27). By contrast, data from a Swedish BPSD registry indicated that anxiolytics, but not hypnotics, were associated with increased mortality (33). A smaller cohort study which recruited from community and residential settings and provided two years of follow-up reported a decreased risk in benzodiazepine users (41). In a Japanese, hospitalised cohort, neither benzodiazepines, hypnotics, anxiolytics, and sedatives (HAS) predicted time from admission to death (52). Study without a placebo arm In a Canadian study involving nursing home residents, residents prescribed benzodiazepines and other hypnotic agents did not identify a difference in risk of non-cancer mortality relative to those prescribed atypical antipsychotics (Rate ratio: 1.21, 95% CI:0.87-1.68) (23). Studies reporting mortality in specific groups Among people with dementia hospitalised in the UK with covid between 2020-2022, covid-specific mortality risk was higher in those prescribed benzodiazepines compared to non-users (aHR 3.00 95% CI: 1.28-7.03) (22). Among participants who experienced a hip fracture, benzodiazepine users did not have higher mortality than non-users (aHR = 1.06 [0.98-1.15]) (24). Studies not reporting hazard ratios A Swedish study found that, in a cohort recruited to explore long-term effects of anti-dementia medication, prescription of anxiolytics, sedatives and hypnotics was associated with shorter survival in nursing homes (mean difference −1.03 years, 95% CI: −1.91 to −0.15; p = 0.022) (44). In a care home cohort originally recruited for an RCT, the odds of death among those prescribed Z-drugs did not differ from the group not prescribed these drugs (43). Case control study In this study, the odds of being prescribed these medications among those who died was higher than for survivor groups (anxiolytics: aOR=1.33, 95%CI 1.25–1.41)(26). GRADE assessment We found weak evidence (downgraded due to inconsistency) that HAS prescribing was not associated with greater all-cause mortality. Opioids and Analgesics ( k = 5) We included one RCT, three cohort studies (Supplementary file E, Figure 4) and one case control study reporting mortality rates associated with opioids and analgesics. An RCT recruited people with dementia and comorbid depression, from 47 Norwegian nursing homes, in a study judged to be at serious risk of bias, finding no significant difference between active analgesic treatment (buprenorphine or paracetamol) and placebo groups (53). In cohort studies, opioid prescribing was not associated with increased mortality, relative to non-users, in patients with dementia hospitalised with covid (aHR: 2.10 95% CI 0.88-4.95) (22); nor was analgesic (unspecified) (aHR: 1.07 95% CI 0.98-1.17) (33). One cohort study found that opioid prescribing was associated with greater risk of mortality after hip fracture (aHR: 1.29 95% CI 1.19-1.40) (24). In a case-control study (54), judged to be at moderate risk of bias, the odds of being prescribed buprenorphine were higher among survivors versus people with dementia who had died (OR) of 2.32 (95% CI: 0.98 to 5.49). GRADE assessment Across all study designs, the evidence that prescribing was not associated with increased mortality was weak. The certainty of evidence was downgraded for RCTs, case-control, and cohort studies due to risk of bias and imprecision. Section 4: Mood stabilisers and Antiepileptics ( k =6) Of six studies, five were cohort studies (Supplementary file E, Figure 5). One cohort study (discussed above) involving people with dementia hospitalised with covid mood stabilisers was not associated with increased mortality (aHR=1.44, 95%CI 0.62-3.60), relative to non-users, in patients with dementia hospitalised with covid (22). Another study found that valproic acid was associated with a non-significant trend (aRD=4.1, 95%C1 -1.0-9.2) toward increased mortality (42). Two studies involving a large Finnish cohort of people with Alzheimer’s disease dementia reported (in overlapping samples) that anti-epileptic prescribing predicted mortality (aHR=1.15, 95%CI 1.05-1.28) (49), with the study with a smaller sample size finding a similar increased risk, that approached significance (aHR=1.12, 95%CI 0.99-1.280, among people after a hip fracture (24). In the fifth study, antiepileptic prescribing did not predict greater mortality risk (aHR=0.92, 95%CI 0.17-1.12) (33). The case control study found a significant association between mood stabiliser use and lower mortality (OR=0.78, 95%CI 0.81-0.76). It was rated as having serious risk of bias, primarily due to inadequate control for confounding variables (54). GRADE assessment The evidence was weak across all study designs. We downgraded the certainty of evidence for the RCT and cohort studies due to imprecision, and for the case–control study due to risk of bias and imprecision. In one study, there was a non-significant trend towards greater mortality among those prescribed anti-epileptic medication, and in a large study at moderate risk of bias, anti-epileptic prescribing was also associated with mortality. Mixed psychotropic medications A study involving US community dwelling veterans with mild dementia, ‘sedative related’ medications, which included anticonvulsants, benzodiazepines, muscle relaxants, hypnotics-barbiturates, gabapentin, analgesics, narcotics and opioids, were not significantly associated with six-year mortality (55). GRADE assessment The evidence was weak, and downgraded due to imprecision. Discussion This systematic review examined mortality risks associated with psychotropic medications commonly substituted for antipsychotics for the management of BPSD. We identified 36 eligible studies, with most studies focusing on antidepressants. We found weak evidence of a trend in those prescribed antidepressants towards greater mortality risk in RCTs, and lower risk in naturalistic cohort studies, and that HAS prescribing was not associated with greater all-cause mortality. Evidence for mood stabilisers/antiepileptics and opioids/analgesics was limited and inconsistent. Findings of a lack of clear association between prescribing and mortality should not be interpreted as evidence of safety or harm. Only three studies were rated as being at low risk of bias. Methodological limitations include wide confidence intervals, between-study heterogeneity (in population studied, dementia subtype, covariates adjusted, differences in drug type and dosage, and follow-up duration), and susceptibility of observational studies (which comprised most evidence identified) to bias and confounding. In many studies, exposure misclassification and immortal time bias limited interpretation. Only one cohort study was judged to have adequately addressed key confounders, and it attempted to reduce confounding by indication using propensity score matching (23). Consequently, the hypothesis that substitute psychotropic prescribing may increase mortality risks cannot be discarded. These drugs are also associated with faster cognitive decline (56), hip fracture (57,58) and falls (59). Divergent trends between study designs were observed, with RCTs suggesting a greater mortality risk associated with antidepressants, while cohort studies suggested a lower risk. This discrepancy may reflect confounding in observational estimates. In cohort studies, antidepressant prescribing may be influenced by a lower likelihood of treatment receipt and shorter life expectancy among under-served groups (60). Prescribing decisions may also reflect a rational reluctance to treat individuals at higher risk of adverse effects due to greater physical and cognitive morbidity (61). Antidepressants may be less effective in people with dementia compared with people without cognitive impairment (28,29). Non-pharmacological interventions are prioritised as first line approach to manage BPSD (8). However, few people with depression and dementia are able to access individual psychological therapy (12), despite such approaches may be effective (62,63). Strengths and limitations To our knowledge, this is the first systematic review examining mortality risks across the multiple classes of psychotropic medications commonly prescribed as alternatives to antipsychotics in people with dementia. It has several limitations. Meta-analysis was not possible owing to substantial variability between studies in methodological design, populations, outcomes, and definitions of drug exposure. A recent large-scale registry study found a dose-response relationship between selective serotonin reuptake inhibitors (SSRI) dosage and all-cause mortality, but not for other drug types (56), suggesting that mortality risks may vary by antidepressant type and dose. We could not account for this, as few included studies reported dosages. Few studies reported treatment adherence or duration. Reasons for prescribing were often unreported, so medications may have been prescribed for indications other than BPSD. The 12-month, median follow-up limited the mortality that could be observed. Small sample sizes with few deaths may yield underpowered and unstable estimates. Only a portion of observed mortality is likely attributable to the short- or moderate-duration drug exposure typical in this population. Finally, some covariates related to mortality were not considered, such as lifestyle and exercise. Conclusions We found weak evidence that antidepressants or hypnotic/sedative/anxiolytics prescribing was not associated with greater mortality, but methodological limitations preclude interpretating this as evidence of safety. Evidence for other drug classes was sparse and inconclusive. Future studies should examine how drug types and dosages, treatment duration and adherence, influence within-class variation in mortality risk. Robust real-world studies (including target trial emulations and new-user, active-comparator designs with time-varying exposure) could mitigate for the paucity of RCT evidence and practical challenges of powering trials for mortality. Pragmatic or registry-based randomised evaluations of treatments may be a feasible strategy for assessing mortality risks. Declarations Role of the funding source The study funders had no role in study design, data collection, analysis, interpretation, or writing of the report. Data availability The dataset generated and analysed during the current study are available from the corresponding author on reasonable request. Competing interests All authors declare no financial or non-financial competing interests. Funding : This review is funded by the NIHR Three Schools’ Dementia Research Programme, as part of the QEMISTRY-Dementia: Quantifying and Explaining MortalIty aSsociaTed with PsYchotropic Drug Prescribing in Dementia study. PROSPERO registration : CRD42024602796 References GOV.UK [Internet]. [cited 2025 Aug 6]. Health matters: midlife approaches to reduce dementia risk. Available from: https://www.gov.uk/government/publications/health-matters-midlife-approaches-to-reduce-dementia-risk/health-matters-midlife-approaches-to-reduce-dementia-risk CF. The growing impact of dementia and the importance of early diagnosis [Internet]. CF. 2024 [cited 2025 Aug 6]. 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Tables Table 1 Study characteristics and results for Randomised Controlled Trials Study Setting, country Total sample size Dementia type, indication Sex (f), Ethnicity (white) (n, %) Intervention arm n Control n Treatment duration Follow up time for mortality outcome Mortality rate intervention vs control Statistical analysis Banerjee (2021)(28) 26 NHS clinical centres, UK 204 AD, agitation 135 (66.2%), NR Mirtazapine 102 Placebo 102 12 weeks 16 weeks 7/102 (6.86%) vs 1/102 (0.98%) Fisher’s exact test p=0·065 Banerjee (2011)(29) 9 NHS clinical centres, England 326 AD, depression 221 (67.8%), 303 (92.9%) Sertraline 107 Placebo 111 39 weeks 39 weeks 5/107 (4.67%), 5/108 (4.63%) vs 5/111 (4.5%) ND Mirtazapine 108 Erdal (2018) (53) 47 nursing homes, Norway 162 All cause dementia, depression 122 (75.3%), NR Paracetamol 36 Placebo 37 13 weeks 13 weeks NR Pearson x 2 test; p = 0.447 Buprenorphine 44 Placebo 45 UK United Kingdom; AD Alzheimer’s disease; ND not done; NHS, National Health Service; NR not reported; Table 2 Study characteristics and results for case control studies, investigating odds of mortality associated with non-antipsychotic prescribing in populations with dementia Study Country Dementia sample population Case n Control n Follow up time Risk of mortality associated with psychotropic prescribing (adjusted) Covariates adjusted for Johnell (2017) Sweden (26) Patients from all inpatient and specialized outpatient care in Sweden; aged 65+ with dementia Died in 2011 (except suicides & undetermined deaths) 10,341 Alive end of 2011; matched by age, sex & case event day 24,880 1 year Antidepressant aOR: 1.14; [CI] 1.08–1.21 Anxiolytics aOR: 1.33; [CI] 1.25–1.41 Education level, inpatient days, Charlson co-morbidity index, co-prescribing (including antipsychotics) Roach (2023) (54) Australia Care home residents referred to Dementia Support Australia Died November 2015-16 44 Alive; sex matched 44 12 months Regular benzodiazepine use: OR 5.62; [CI] 2.17-14.48, p = 0.0004 Buprenorphine: OR 2.32 [CI]0.98–5.49 AD: OR 1.58 [CI]0.68–3.66 Mood stabilisers: OR 0.25 [CI]0.81–0.76 / n sample size; AD antidepressant; aOR adjusted odds ratio; ns not significant; OR odds ratio Table 3 Study characteristics and results for cohort studies Study Country Design Dementia sample population n Female (n,%); White majority ethnicity (n,%) Medication (category *) Follow up, mortality outcome Mortality risk (adjusted); aHR (CI) unless stated Covariates adjusted for Barrett (2020)(55) USA Community dwelling veterans aged 60+ with mild dementia from memory clinic 143 14 (9.8%), 134 (94.4%) (1) anticholinergic (mixed) 6 years χ 2 (1) =3.30, P=0.07 None (2) sedatives (mixed) χ 2 (1) =0.13, P= 0.72 Bishara (2022) (46) UK Patients aged 50+; first dementia diagnosis, London 2ndry psychiatric services 2008 – 17; any antidepressant at baseline 4,380 2,847 (65%), 3,364 (76.8%) (1) no cholinergic burden (AD) 3 years (SD +/- 2.3) (3) vs (2/3): 0.88 (0.79-0.98) Age, sex, ethnicity, marital status, MMSE, deprivation, antipsychotics, HoNOS scores, AChEI, cardiovascular disease (2) Intermediate burden (AD) (2) vs (1): 0.97 (0.84-1.13) (3) High burden (AD) (3) vs (1): 0.86 (0.72-1.02) Brännström (2017) (41) Finland and Sweden Participants with dementia from: epidemiological study inviting residents aged 85+, in selected municipalities; observational study and 2 RCTs in Sweden: nursing home residents, age ≥ 65 years, ADLs dependent, MMSE ≥ 10 1037 769 (74.2%), NR AD 2 years 0.96 (0.78-1.17), p=0.05; men: 0.61 (0.40–0.92); women: 1.09 (0.87–1.38) Age, sex, comorbidities, prescribed drugs, Barthel ADL Index, BMI, GDS-15, MMSE Benzodiazepines (HAS) 0.72 (0.54-0.96), p=0.96; men: 0.81 (0.45-1.45); women: 0.73 (0.53-1.02) Bränsvik (2021) (33) Sweden Individuals with all cause dementia who were registered in the BPSD registry 2010–13 (national registry to support nursing home management of BPSD) 11,448 7485 (65.4%), NR Analgesics (OA) mean (SD) 250.3 (191.6) days, 1.07(0.98 –1.17), p=0.14** Age, sex, dementia diagnosis, medication, previous myocardial infarction, hip fracture and stroke. Antiepileptics(MA) 0.92 (0.75-1.12) p=0.40** Anxiolytics (HAS) 0.90 (0.81-1.01), p=0.07** Hypnotics (HAS) 0.99 (0.88-1.11), p=0.89** AD 0.81(0.74-0.89), p <.001** Chen (2023) UK (22) Patients with dementia admitted to one UK hospital with first covid infection 23.3.20 – 10.4.22 formed the “exposure cohort”; compared to a control cohort without covid 1,490 890 (59.7%), 1,190(79.9%) Benzodiazepine (HAS) 239.4 (237.0) days 3.00 (1.28-7.03), p<0.5*** Age, sex, marital status, ethnicity, physical comorbidity, psychotropic co-prescribing Antidepressant (AD) 1.16 (0.54-2.51)*** Opioid drugs (OA) 2.10 (0.88-4.95)*** Antiepileptic (MA) 1.49 (0.62-3.60)*** Connors (2016) Australia (50) Patients from nine memory clinics with all cause dementia, living in the community receiving <40 hours a week nursing care. 779 371 (47.6%), NR Benzodiazepines (HAS) 8 years 0.91 (0.66–1.26), p = 0.56 Age, sex, marital status, dementia type, cognition, dementia severity, NPS, number drugs, antipsychotics Cullum (2020) New Zealand (51) Patients with all cause dementia recruited from South Auckland memory service in, 2013-17 475 271 (57.05%), NR Benzodiazepines (HAS) To death/ last contact, up to 2019 0.89 (0.48-1.64), p = 0.699 Age, sex, ethnicity, dementia type, cognitive score, comorbidity, AChEI, antipsychotics Enache (2016) Sweden (30) Memory clinic patients with all cause dementia, from SveDem registered 2007-2013 linked to the prescribed drug register. 20,050 11,642 (58.1%), NR AD One year 0.92 (0.86-0.99), p<0.05. Age, sex, number of medications, MMSE, living in home or nursing home, dementia subtype. Feresh-tehnejad (2018) Sweden (31) Patients from the SveDem; registered 2007–2015 from memory clinics and primary care units: with DLB 1,110 430 (38.7%), NR AD Median survival: 4.0 years 0.85 (0.67-1.09) Age, sex, number of medications, MMSE Patients from the SveDem; registered 2007–2015 from memory clinics and primary care units: with PDD 764 275 (36.0%), NR AD Median survival: 4.1 years 1.76 (1.28–2.42), p = 0.001. Huang (2015) USA (34) 2006-2009 Medicare data of nursing home residents with Alzheimer’s disease and related dementias 1,661 1176 (70.8%), 1425 (85.8%) AD 6 months 0.82 (0.70–0.97) Age, sex, race, ethnicity, region, income, NPS, comorbidity, function, hospital or nursing facility stay, co-medications Huybrechts (2011) Canada (23) Individuals aged 65+, admitted to British Columbia nursing home 1/1/1996 – 31/3/2006. 4,043 NR for the subgroup with dementia AD vs antipsychotics 180 days RR 1.22 (0.88–1.70)***** Age, sex, year, comorbidities, prior medication use. Benzodiazepines vs antipsychotics (HAS) RR 1.21 (0.87–1.68)***** Kazmierski (2018) Greece (38) Patients with Alzheimer’s disease/ related dementia from Memory Clinic / day centres, taking AChEI 1171 725 (62%), NR AD 2 years 0.90 (0.58-1.41), p= 0.66 None Anxiolytics (HAS) 0.59 (0.29-1.23), p=0.16 Kollhorst (2019) Germany (45) Individuals were AD initiators (2005–2015), aged 65+, had 1-year continuous insurance and ≥1 hospital or outpatient depression diagnosis and dementia. 50,511 NR for the subgroup with dementia Escitalopram (AD) Median: 51–233 days 0.96 (0.85–1.08)**** Age, sex, comorbidities, frailty indicators, and co-medications. Sertraline (AD) 0.99 (0.91–1.07)**** Fluoxetine (AD) 0.98 (0.82–1.18)**** Paroxetine (AD) 0.89 (0.73–1.08)**** Venlafaxine (AD) 0.95 (0.83–1.09)**** Duloxetine (AD) 0.83 (0.69–0.99)**** Amitriptyline (AD) 1.15 (1.05–1.25)**** Doxepin (AD) 0.85 (0.72–0.99)**** Trimipramine (AD) 0.77 (0.63–0.95)**** Opipramol (AD) 0.87 (0.76–1.00)**** Mirtazapine (AD) 0.97 (0.92–1.02)**** St. Johns Wort (AD) 0.55 (0.46–0.67)**** Lewis (2018) UK (40) Secondary mental healthcare patients diagnosed with dementia, Camden and Islington NHS trust London. 2008-2016. 3374 2045 (61%), white 2693 (79.82%) AD mean 3.22 (SD 2.16) years 1.15 (0.99-1.33), p =0.059 Age, sex, ethnicity, marital status, IMD tertiles, MMSE, depression Maust (2015) USA (42) Veterans’ health registries data: patients aged 65+ with dementia and ≥1 inpatient or outpatient episode, 1998-09. 46,008 1,150 (2.5%), 32,707 (71.1%) AD 180 days aRD: 0.6 (0.3-0.9), p<.01 Age, sex, marital status, mental conditions, medication, healthcare use, comorbidities Valproic acid (MA) aRD: 4.1 (-1.0-9.2) McMichael (2020) UK (27) All patients in Northern Ireland that received antidementia medication (cholinesterase inhibitors and memantine) 2010-2016 25418 16537 (65%), NR Hypnotics and anxiolytics (HAS) 7 years 1.08 (0.98–1.19) Age, sex, marital status, deprivation measure, urban/rural classification, comorbidity, medications. AD 1.08 (0.99–1.17) McMichael (2021) UK (39) AD 1.12 (0.94–1.33) Age, sex, marital status, urban/rural, area deprivation Mostafaei (2023) Sweden (32) Patients diagnosed with dementia in the SveDem registry between 2007–2018; aged 65+ at diagnosis. 28023 16273 (58.07%), NR AD Median follow-up time: 1053 days for survivors, 1125 days for deceased Elastic-net logistic regression: importance value 3%. 0.135 Age, sex, MMSE, BMI, comorbidity, dementia type, comorbidities, dementia medications, number of medications, referral to diagnosis time, physiotherapist assessment, residence, alcohol diagnosis Mueller (2017) UK (36) Mild Alzheimer’s disease diagnosed at South London outpatient services 2006-16 5473 3504 (64.02%), 4312 (78.78%) AD Mean 3.5 years SD 2.4 years 1.25 (1.06-1.48) Age, sex, ethnicity, marital status, deprivation, cognitive scores, HoNOS-65+ subscales, comorbidity Mueller (2018) UK (37) Aged 65+, Alzheimer’s disease from South London outpatient services 2008-12 2464 1642 (66.6%), 2014 (81.8%) AD Mean 3.7 SD 1.7 years. 1.16 (0.99–1.37) Age, sex HAS 1.28 (1.02–1.62), p < 0.05 Richardson (2021) (43) WHELD cluster RCT, residents with dementia in 69 care homes in England (2013-15) 926 659 (71%) 877 (95%) Z-drugs (HAS) 9 months Odds Ratio (death in z-drug vs non-users): 0.66 (0.38 to 1.15) Age, sex, ethnicity, marital status, CDR, Abbey Pain Scale score, comorbidity and co-medication use Richardson (2020), UK (47) People diagnosed with dementia between January 2000-March 2016, aged 55+ from CPRD data linked to HES data in England. Those newly prescribed z-drugs and non-sedative-users with sleep disturbance. 5356 3232 (60.3%), 4611 (86%) Z-drug vs non-users with sleep deprivation (HAS) Median (IQR) of 3.5 (3.0–10.3) months 1.38 (1.14-1.66) Age, sex, health behaviours, immunisations, dementia subtype, sleep disturbance severity, comorbidities, medical history, concurrent medication use. Z-drugs vs matched controls with proximal GP consultation (HAS) 1.08 (0.94–1.23) Z-drugs vs benzodiazepines (HAS) 0.73 (0.64–0.83) Saarelainen (2018) Finland (48) MEDALZ cohort of community dwelling people diagnosed with Alzheimer’s disease 2005-11 31,140 (users/ matched non-users 19,592 (62.9%), NR Benzodiazepines (HAS) 180 days 1.59 (1.35‐1.88) Comorbidity, socio-economic status, prior opioid, antidepressant, antipsychotic, use. Z-drugs (HAS) 1.06 (0.83‐1.35) Benzodiazepines and related drugs 1.40 (1.25‐1.57) Sarycheva (2020) Finland (49) 11,276 (users/ matched non-users) NR Anti-epileptic (MA) 3 years 1.16 (1.05–1.28) Age, sex, medication use, medical history, psychiatric history, substance abuse. Pregabalin 0.51 (0.42–0.63) % Carbamazepine 0.91 (0.67–1.25) % Clonazepam 0.44 (0.26–0.76) % Oxcarbazepine 0.93 (0.65–1.32) % Gabapentin 0.40 (0.26–0.62) % Phenytoin 0.63 (0.37–1.07) % Su (2019) (35) Taiwan Patients aged 60+, diagnosed with dementia 2000-11, then diagnosed with depression 44,116 14,218 (54.92%), NR AD (lower dose) Until 2013 0.98 (0.93-1.03), p = 0.33 Age, sex, urbanization, income, date AD (higher dose) 0.65 (0.62-0.69), p<0.0001 Tolppanen (2016) Finland (24) MEDALZ cohort of community dwelling people with Alzheimer’s disease 2005-2011, who sustained a first hip fracture in observation period 4,851 NR AD 1.3 years (range 1 day-7.7 years) 0.97 (0.89-1.05) Occupational social class Benzodiazepines (HAS) 1.06 (0.98-1.15) Opioids (OA) 1.29 (1.19-1.40) Antiepileptic (MA) 1.12 (0.99-1.28) Toshie (2019) (52) Japan Patients hospitalized in Toyohashi (2012–16), post-mortem dementia diagnosis, available medication data 76 44 (57.9%), NR Benzodiazepine (HAS) Admission to death 1.07 (0.56 -2.03, p=0.84 Age, sex HAS 1.00 (0.57-1.75), p=0.99 Watt (2018) Canada (44) Adults with dementia, aged 66+ living in long term care, with new prescription of trazadone or AA, 2009-15 6588 trazadone2875 AA 6502(68.7%), NR Trazadone (AD) vs AA 90 days 0.75 (0.66-0.85) Age, sex, function, health care use, medication use, medical history, performance scales. Wattmo (2016) (64) Sweden People with Alzheimer’s disease recruited in 1997 for open AChEI study; who died while living in a NH; MMSE 10-26 at baseline 220 161 (73%), NR HAS Until 31.12.14 MD: −1.03 (−1.91-−0.15); p =0.02 Sex, living status, antihypertensive/ cardiac therapy, ADL at nursing home placement * Categories in which medication analysed in this paper: AD: antidepressants; HAS: Hypnotics, Anxiolytics, Sedatives; MA: Mood stabilisers/ antiepileptics; Mixed; OA: Opioids/analgesics; see Supplementary file D for details of all medications included ** Association between BPSD and mortality adjusted for drug of interest; *** aHR (case-control comparing exposure/ non-exposure cohorts) = 4.44, [CI] 3.13–6.30; additional risk associated with drug of interest shown: **** risk compared with citalopram; *****Noncancer related mortality; % : relative to valproic acid AA: Atypical Antipsychotics; AChEI : anticholinesterase inhibitors; aRD: Associated Risk Difference; aHR: Adjusted Hazard Ratio; CI: Confidence Interval; DLB: Dementia Lewy Body; HoNOS : Health of the National Outcome Scales; IMD: Index of Multiple Deprivation; MD: Mean difference in years lived; MMSE: Mini Mental State Examination; NPS: Neuropsychiatric Symptoms; PDD: Parkinson’s Disease Dementia; RR: Relative Risk Note: all numerical values shown to 2 decimal places Additional Declarations The authors declare no competing interests. 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Diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9539696/v1/a8eaf67111b4af039f073e02.png"},{"id":108490925,"identity":"8a5b405c-30f4-4075-a1f9-37546e96cd26","added_by":"auto","created_at":"2026-05-05 09:50:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":612916,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9539696/v1/91d87956-1522-4b3b-a30e-705cd8c9e261.pdf"},{"id":108012912,"identity":"1a1f00f6-ef8c-4c67-8bfb-8a5accde243c","added_by":"auto","created_at":"2026-04-28 13:16:49","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":604412,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryfileBMJMentalHealth.docx","url":"https://assets-eu.researchsquare.com/files/rs-9539696/v1/7c9a16dd4a3575fa3255f91f.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eMortality risk associated with psychotropic medications frequently substituted for antipsychotics to manage behaviours that challenge in people with dementia: a systematic review\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn the United Kingdom (UK), an estimated 982,000 people have dementia. This is projected to exceed 2 million by 2050 (1), with societal dementia costs rising to \u0026pound;90 billion by 2040 (2). Three-quarters of people with dementia experience clinically significant behavioural or psychological symptoms of dementia (BPSD) such as agitation, depression, and anxiety (3). BPSD occur across all dementia subtypes (4), reduce quality of life (5) and increase care costs (6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAntipsychotics were a mainstay of BPSD management until concerns arose about their safety and effectiveness. A 2009 report estimated they contributed to 1,800 excess deaths annually, and increased cognitive decline and falls risk among people with dementia (7). National Institute for Health and Care Excellence guidelines recommend psychological approaches as first-line treatment for BPSD, because they are usually safer and more effective (8).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBecause of concerns about increased mortality, prescribers often substitute other drugs for antipsychotics. UK and Dutch primary care studies show that in people with dementia, antidepressant prescribing has increased as antipsychotic use has decreased since 2009\u0026nbsp;(9\u0026ndash;11). This shift in prescribing was not matched by investment in access to psychological therapies. Older adults, especially those with dementia, struggle to access effective non-pharmacological therapies (12), and psychotropic use remains high. In an English care home study in 2014-15, 58% of residents with dementia were prescribed psychotropic medication, most commonly anxiolytics or hypnotics (13).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile often perceived as safer, psychotropic drugs substituted for antipsychotics in people with dementia may also carry risks, including increased mortality (14\u0026ndash;16). To our knowledge, no systematic review has explored these potential associated mortality risks. This study systematically reviewed studies published since the 2009 report, exploring mortality risks associated with psychotropic medication (other than antipsychotic drugs) used to manage BPSD in people with dementia.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe preregistered this systematic review on PROSPERO (CRD42024602796) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Supplementary file A)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch strategy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe searched four electronic databases, PsycINFO, Web of Science, PubMed and Scopus, from 1.1.2010 until 31.10.2024, adapting the search strategy for each database to include terms related to psychotropic medication, dementia, mortality and study design (Supplementary file B). We conducted forward and backward citation searches for eligible studies. No limits were placed on language.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy selection\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing Covidence, two reviewers (from GS, HDK, CC, MY) independently screened titles and abstracts, then reviewed full text articles against eligibility criteria to identify relevant studies. Disagreements were resolved through discussion with a third independent reviewer (HDK or CC). \u003c/p\u003e\n\u003cp\u003eWe included randomised controlled trials (RCTs), cohort studies and case-control studies, quantitatively reporting mortality risks (compared to placebo or another drug) associated with psychotropic drugs, including antidepressants, anxiolytics, mood stabilisers, sedatives or analgesics, in a study population or separately analysed subgroup diagnosed with any dementia subtype. Studies focusing on antipsychotic medication (in line with our aim) or anti-dementia medications (prescribed primarily for cognition, rather than BPSD) were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData extraction\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extracted data regarding study design, sample characteristics, psychotropic medication, follow up, and mortality risk estimates (risk ratio [RR] or hazard ratio [HR] where available, and where only cross-sectional data were available, odds ratio [OR]) associated with relevant medication and the covariates adjusted for in analyses. GS extracted all data, and MY independently extracted a 20% subset to ensure accuracy and consistency. We contacted authors of eligible studies to obtain missing data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias and GRADE (Grade of Recommendations Assessment, Development and Evaluation)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo reviewers (from GS, CC, HDK, YL, MM) independently assessed risk of bias of included studies (Supplementary file C), resolving discrepancies through discussion with a third independent reviewer (HDK or CC). We used the Cochrane Risk of Bias 2 (RoB 2) for RCTs to evaluate internal validity. In line with tool procedures, each domain and overall risk of bias were rated as \u0026lsquo;low risk\u0026rsquo;, \u0026lsquo;some concerns\u0026rsquo;, or \u0026lsquo;high risk\u0026rsquo;(17). For observational cohort and case control studies, we used the Newcastle-Ottawa Scale. We defined good quality cohort studies as 3+ stars in the selection domain, 1+ stars in comparability domain and 2+ stars in the outcome/exposure domain (18). In the comparability domain, we considered both measured confounders and time-related biases. Measured confounders included age, gender, and confounding by indication. Time-related biases encompassed factors such as the definition of time zero and the handling of time-varying exposures, including immortal time bias. Two reviewers (YL, ES) independently determined the quality of evidence using GRADE, and discussed with co-authors to reach consensuses (19). For case control studies we rated studies scoring 7+ as low risk of bias, 5-6 as moderate and others as high risk of bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData synthesis and visualisation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe used the \u003cem\u003emetafor package\u0026nbsp;\u003c/em\u003e(20) in R (version 4.4.1) for synthesis and visualisation (21). We intended to meta-analyse findings, but as study quality and heterogeneity precluded this, we used this package to generate forest plots to display data only and we summarised studies narratively. Original mortality risk estimates were grouped by drug class and we draw forest plots for RCTs (RRs), cohort studies (HRs), and case-control studies (ORs), only for descriptive purposes. When effect sizes were not reported, other available data were used for calculations.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSearch findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e34 out of 6,107 unique articles met eligibility criteria: three RCTs, 29 cohort studies, and two case-control studies (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy and population characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample sizes ranged from 76 to 67,072 (median: 3,374). Median follow-up duration was 12 months (range 3 to 96)\u003cem\u003e.\u003c/em\u003e Studies included individuals with all-cause dementia (k=23), or specific dementia subtypes: Alzheimer\u0026rsquo;s (k=10), Parkinson\u0026rsquo;s disease and Lewy body dementia (k=1). Associations were reported with all-cause mortality (k=31); \u0026nbsp;covid-related excess mortality (22), non-cancer (23) or hip fracture-related mortality (24). 22/29 (75.9%) cohort studies recruited prevalent users, Twenty-three studies (79.3%) implemented methods to address or mitigate immortal time bias, and two (6.9%) modelled drug use as a time-varying exposure. Study characteristics are presented in Tables 1-3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePsychotropic drug classes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe reported mortality estimates in included studies, based on British National Formulary classifications (25):\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eAntidepressants (\u003cem\u003ek\u003c/em\u003e=25)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHypnotics, anxiolytics, sedatives (\u003cem\u003ek\u003c/em\u003e=16)\u003c/li\u003e\n \u003cli\u003eOpioids/ analgesics (\u003cem\u003ek\u003c/em\u003e=5)\u003c/li\u003e\n \u003cli\u003eMood stabilisers/ antiepileptics (\u003cem\u003ek\u003c/em\u003e=6)\u003c/li\u003e\n \u003cli\u003eMixed (\u003cem\u003ek\u003c/em\u003e=1)\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eSupplementary file C details the medications studied. Thirteen studies fully specified drugs included in analysed categories, while 11 only reported broad categories (e.g. \u0026lsquo;benzodiazepines\u0026rsquo;, \u0026lsquo;antidepressants\u0026rsquo;). Other studies provided World Health Organisation-developed, anatomical therapeutic chemical classification (ATC) system codes (26) or specified British National Formulary sections for included drugs (27).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the three RCTs, one was \u0026ldquo;low risk\u0026rdquo;, one had \u0026ldquo;some concerns\u0026rdquo;, and another was rated \u0026ldquo;high risk\u0026rdquo; of bias (Supplementary file D, Table 1). Of 29 cohort studies, all but one received a \u0026ldquo;high risk\u0026rdquo; rating, in almost every case due to low scores in the comparability domain (Supplementary file D Table 2). Of the two case-control studies, one was rated \u0026lsquo;low, and one \u0026lsquo;moderate risk\u0026rsquo; (Supplementary file D, Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAntidepressants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRCTs\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo double-blind RCTs conducted in England assessed the impact of mirtazapine on all-cause mortality (Supplementary file E, Figure 1). One study judged low risk of bias observed higher mortality in the mirtazapine relative to placebo arm (RR=7.0, 95%CI 0.9-55.9). However, the confidence interval was wide. (28). Another RCT found no difference in mortality between sertraline, mirtazapine or placebo (29).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCohort studies\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirteen studies reported HRs for the relationship between antidepressant use and all-cause mortality; these findings are summarised in Figure 2 in Supplementary file E. Overall, the evidence is mixed with some studies suggesting a protective, others a harmful effect. However, no clear pattern emerged.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThree studies reported overlapping samples from Swedish national registry data collected since 2007; this dataset includes 90% of those diagnosed with dementia in Swedish memory services and 60% in primary care. The largest of these, which included patients with all-cause dementia (2007-13), found a lower mortality risk in memory clinic patients with dementia prescribed antidepressants compared to non-users, a year after dementia diagnosis (HR=0.92, 95%CI 0.86-0.99) (30). Two further studies reported increased mortality with antidepressant use in people with Parkinson\u0026rsquo;s disease dementia (HR=1.76, 95%CI 1.28-2.42), but not Lewy body dementia (HR=0.85, 95%CI 0.67-1.09) (31); and a forth study, using machine learning, that antidepressant use was a weak or non-significant predictor of mortality (32).\u003c/p\u003e\n\u003cp\u003eThree additional studies reported that antidepressants were associated with a lower mortality risk, including a \u0026nbsp;Swedish registry data study (33), USA Medicare data of long-stay nursing home residents (34), and people with depression and dementia prescribed higher antidepressant doses in a Taiwan National insurance database (35). Two studies with overlapping populations using linked UK electronic health records found that taking antidepressants (before or after, or only after dementia diagnosis) predicted higher mortality compared to non-users (36), with similar, non-significant findings in a second study (37).\u003c/p\u003e\n\u003cp\u003eFive studies found no association between antidepressant prescribing and mortality. These involved: patients with dementia receiving antidementia medication in Greece (38); and Northern Ireland (27,39); and UK secondary mental healthcare patients with dementia (40); cohorts of community and nursing home residents with dementia in Finland and Sweden (41); and a Finnish community population with Alzheimer\u0026rsquo;s disease followed up after a hip fracture (24).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo studies did not report HR. One, a US study including patients from the Veterans Health Registries data, reported a lower mortality risk associated with antidepressant use compared with antipsychotics and valproic acid (42). The other, based on UK primary care and hospital records of those with dementia and sleep disturbance, found no increased mortality risk associated with low dose tricyclic antidepressants (43).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudies without a placebo arm\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn one of only two cohort studies judged to be at lower risk of bias, a Canadian nursing home study used medical records to compare outcomes between residents who were prescribed an antidepressant within the first 90 days of admission to those who were prescribed an atypical antipsychotic, and found a non-significant trend towards increased mortality in those prescribed antidepressants (23). By contrast, a second Canadian study compared adults with dementia living in long-term care with a new prescription of trazadone or atypical antipsychotics, finding a lower risk of mortality in people taking trazadone versus those taking atypical antipsychotics\u0026nbsp;(44).\u0026nbsp;A study using the German Pharmaco-epidemiological Research Database compared mortality risks of twelve different antidepressants with citalopram in patients with depression. Duloxetine, doxepin and trimipramine were associated with a lower risk, and amitriptyline a higher risk of mortality, compared with citalopram (45). Another study found no increase in mortality among patients with dementia in secondary psychiatric services taking antidepressants with higher versus lower cholinergic burden (46).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCovid-related mortality\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOne study compared an \u0026ldquo;exposure cohort\u0026rdquo; of people with dementia discharged from UK hospitals in 2020-22 after a covid illness requiring hospitalisation, to up to ten matched controls admitted with non-covid illnesses. The risk of mortality was higher among those admitted with covid (aHR=4.44, 95%CI 3.13\u0026ndash;6.30); but did not find a greater mortality among those prescribed an antidepressant relative to those who were not (aHR=1.16, 95%CI 0.54-2.51) (22).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCase control study\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a study using Swedish health service data (n=10,341), cases had higher mortality odds (aOR = 1.14, [CI] 1.08-1.21) than age- and sex-matched controls (26).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGRADE assessment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe found weak evidence (downgraded due to inconsistency and imprecision) of a trend towards greater mortality risk in those prescribed antidepressants in RCTs, and lower risk in those prescribed antidepressants in cohort studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHypnotics, Anxiolytics, and Sedatives (k=16)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMost drugs included in these categories were benzodiazepines; others were Z-drugs. There were 15 cohort and one case control study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCohort studies\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTen studies reported HR and are included in the forest plot (Supplementary file E, Figure 3). Of these, three reported an increased mortality risk. In a primary care national dataset from England, among people with dementia and sleep disturbance, those newly prescribed z-drugs had greater mortality risk than those not on sedative hypnotic medication (aHR=1.38, 95%CI 1.14-1.66) (47). Among people with Alzheimer\u0026rsquo;s disease from a London NHS trust, those taking hypnotics and anxiolytics medications prior to diagnosis had an increased mortality risk compared to non-users (37). A study involving the Finnish MEDALZ cohort of community-dwelling people with Alzheimer\u0026rsquo;s disease found a significant increase in risk of mortality over six months for users of benzodiazepines and Z-drugs (BZDRs), and, for benzodiazepines, compared to non-users (48). One study that included a subgroup of these participants reported similar findings (49).\u003c/p\u003e\n\u003cp\u003eSeven studies reported no increased mortality risk. Specifically, no increased mortality risk associated with the prescription of hypnotic, sedative, or anxiolytic medications relative to non-use was observed among patients recruited from memory clinics in Australia (50), New Zealand (51) or Greece (38), or among people prescribed antidementia medication in Northern Ireland (27). By contrast, data from a Swedish BPSD registry indicated that anxiolytics, but not hypnotics, were associated with increased mortality (33). A smaller cohort study which recruited from community and residential settings and provided two years of follow-up reported a decreased risk in benzodiazepine users (41). In a Japanese, hospitalised cohort, neither benzodiazepines, hypnotics, anxiolytics, and sedatives (HAS) predicted time from admission to death (52).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy without a placebo arm\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn a Canadian study involving nursing home residents, residents prescribed benzodiazepines and other hypnotic agents did not identify a difference in risk of non-cancer mortality relative to those prescribed atypical antipsychotics (Rate ratio: 1.21, 95% CI:0.87-1.68) (23).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudies reporting mortality in specific groups\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong people with dementia hospitalised in the UK with covid between 2020-2022, covid-specific mortality risk was higher in those prescribed benzodiazepines compared to non-users (aHR 3.00 95% CI: 1.28-7.03) (22). Among participants who experienced a hip fracture, benzodiazepine users did not have higher mortality than non-users (aHR = 1.06 [0.98-1.15]) (24).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudies not reporting hazard ratios\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA Swedish study found that, in a cohort recruited to explore long-term effects of anti-dementia medication, prescription of anxiolytics, sedatives and hypnotics was associated with shorter survival in nursing homes (mean difference \u0026minus;1.03 years, 95% CI: \u0026minus;1.91 to \u0026minus;0.15; p = 0.022) (44). In a care home cohort originally recruited for an RCT, the odds of death among those prescribed Z-drugs did not differ from the group not prescribed these drugs (43).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCase control study\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, the odds of being prescribed these medications among those who died was higher than for survivor groups (anxiolytics: aOR=1.33, 95%CI 1.25\u0026ndash;1.41)(26).\u003c/p\u003e\n\u003cp\u003eGRADE assessment\u003c/p\u003e\n\u003cp\u003eWe found weak evidence (downgraded due to inconsistency) that HAS prescribing was not associated with greater all-cause mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOpioids and Analgesics (\u003cem\u003ek\u003c/em\u003e = 5)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe included one RCT, three cohort studies (Supplementary file E, Figure 4) and one case control study reporting mortality rates associated with opioids and analgesics. An RCT recruited people with dementia and comorbid depression, from 47 Norwegian nursing homes, in a study judged to be at serious risk of bias, finding no significant difference between active analgesic treatment (buprenorphine or paracetamol) and placebo groups (53). In cohort studies, opioid prescribing was not associated with increased mortality, relative to non-users, in patients with dementia hospitalised with covid (aHR: 2.10 95% CI 0.88-4.95) (22); nor was analgesic (unspecified) (aHR: 1.07 95% CI 0.98-1.17) (33). One cohort study found that opioid prescribing was associated with greater risk of mortality after hip fracture (aHR: 1.29 95% CI 1.19-1.40) (24).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn a \u0026nbsp;case-control study (54), judged to be at moderate risk of bias, the odds of being prescribed buprenorphine were higher among survivors versus people with dementia who had died (OR) of 2.32 (95% CI: 0.98 to 5.49).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGRADE assessment\u003c/p\u003e\n\u003cp\u003eAcross all study designs, the evidence that prescribing was not associated with increased mortality was weak. The certainty of evidence was downgraded for RCTs, case-control, and cohort studies due to risk of bias and imprecision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSection 4: Mood stabilisers and Antiepileptics (\u003cem\u003ek\u003c/em\u003e=6)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf six studies, five were cohort studies (Supplementary file E, Figure 5). One cohort study (discussed above) involving people with dementia hospitalised with covid mood stabilisers was not associated with increased mortality (aHR=1.44, 95%CI 0.62-3.60), relative to non-users, in patients with dementia hospitalised with covid (22). Another study found that valproic acid was associated with a non-significant trend (aRD=4.1, 95%C1 -1.0-9.2) toward increased mortality (42). Two studies involving a large Finnish cohort of \u0026nbsp; people with Alzheimer\u0026rsquo;s disease dementia reported (in overlapping samples) that anti-epileptic prescribing predicted mortality (aHR=1.15, 95%CI 1.05-1.28) (49), with the study with a smaller sample size finding a similar increased risk, that approached significance (aHR=1.12, 95%CI 0.99-1.280, among people after a hip fracture (24). In the fifth study, antiepileptic prescribing did not predict greater mortality risk (aHR=0.92, 95%CI 0.17-1.12) (33).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe case control study found a significant association between mood stabiliser use and lower mortality (OR=0.78, 95%CI 0.81-0.76). It was rated as having serious risk of bias, primarily due to inadequate control for confounding variables (54).\u003c/p\u003e\n\u003cp\u003eGRADE assessment\u003c/p\u003e\n\u003cp\u003eThe evidence was weak across all study designs. We downgraded the certainty of evidence for the RCT and cohort studies due to imprecision, and for the case\u0026ndash;control study due to risk of bias and imprecision. In one study, there was a non-significant trend towards greater mortality among those prescribed anti-epileptic medication, and in a large study at moderate risk of bias, anti-epileptic prescribing was also associated with mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMixed psychotropic medications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA study involving US community dwelling veterans with mild dementia, \u0026lsquo;sedative related\u0026rsquo; medications, which included anticonvulsants, benzodiazepines, muscle relaxants, hypnotics-barbiturates, gabapentin, analgesics, narcotics and opioids, were not significantly associated with six-year mortality (55).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGRADE assessment\u003c/p\u003e\n\u003cp\u003eThe evidence was weak, and downgraded due to imprecision.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review examined mortality risks associated with psychotropic medications commonly substituted for antipsychotics for the management of BPSD. We identified 36 eligible studies, with most studies focusing on antidepressants.\u0026nbsp;We found weak evidence of a trend in those prescribed antidepressants towards greater mortality risk in RCTs, and lower risk in naturalistic cohort studies, and that HAS prescribing was not associated with greater all-cause mortality. Evidence for mood stabilisers/antiepileptics and opioids/analgesics was limited and inconsistent.\u003c/p\u003e\n\u003cp\u003eFindings of a lack of clear association between prescribing and mortality should not be interpreted as evidence of safety or harm. Only three studies were rated as being at low risk of bias. Methodological limitations include wide confidence intervals, between-study heterogeneity (in population studied, dementia subtype, covariates adjusted, differences in drug type and dosage, and follow-up duration), and susceptibility of observational studies (which comprised most evidence identified) to bias and confounding. In many studies, exposure misclassification and immortal time bias limited interpretation. Only one cohort study was judged to have adequately addressed key confounders, and it attempted to reduce confounding by indication using propensity score matching (23). Consequently, the hypothesis that substitute psychotropic prescribing may increase mortality risks cannot be discarded. These drugs are also associated with faster cognitive decline (56), hip fracture (57,58) and falls (59).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDivergent trends between study designs were observed, with RCTs suggesting a greater mortality risk associated with antidepressants, while cohort studies suggested a lower risk. This discrepancy may reflect confounding in observational estimates. In cohort studies, antidepressant prescribing may be influenced by a lower likelihood of treatment receipt and shorter life expectancy among under-served groups (60). Prescribing decisions may also reflect a rational reluctance to treat individuals at higher risk of adverse effects due to greater physical and cognitive morbidity (61).\u003c/p\u003e\n\u003cp\u003eAntidepressants may be less effective in people with dementia compared with people without cognitive impairment (28,29). Non-pharmacological interventions are prioritised as first line approach to manage BPSD (8). However, few people with depression and dementia are able to access individual psychological therapy (12), despite such approaches may be effective (62,63).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first systematic review examining mortality risks across the multiple classes of psychotropic medications commonly prescribed as alternatives to antipsychotics in people with dementia. It has several limitations. Meta-analysis was not possible owing to substantial variability between studies in methodological design, populations, outcomes, and definitions of drug exposure. A recent large-scale registry study found a dose-response relationship between selective serotonin reuptake inhibitors (SSRI) dosage and all-cause mortality, but not for other drug types (56), suggesting that mortality risks may vary by antidepressant type and dose. We could not account for this, as few included studies reported dosages. Few studies reported treatment adherence or duration. Reasons for prescribing were often unreported, so medications may have been prescribed for indications other than BPSD. The 12-month, median follow-up limited the mortality that could be observed. Small sample sizes with few deaths may yield underpowered and unstable estimates. Only a portion of observed mortality is likely attributable to the short- or moderate-duration drug exposure typical in this population. Finally, some covariates related to mortality were not considered, such as lifestyle and exercise.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe found weak evidence that antidepressants or hypnotic/sedative/anxiolytics prescribing was not associated with greater mortality, but methodological limitations preclude interpretating this as evidence of safety. Evidence for other drug classes was sparse and inconclusive. Future studies should examine how drug types and dosages, treatment duration and adherence, influence within-class variation in mortality risk. Robust real-world studies (including target trial emulations and new-user, active-comparator designs with time-varying exposure) could mitigate for the paucity of RCT evidence and practical challenges of powering trials for mortality. Pragmatic or registry-based randomised evaluations of treatments may be a feasible strategy for assessing mortality risks.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eRole of the funding source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study funders had no role in study design, data collection, analysis, interpretation, or writing of the report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset generated and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial or non-financial competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis review is funded by the NIHR Three Schools\u0026rsquo; Dementia Research Programme, as part of the QEMISTRY-Dementia: Quantifying and Explaining MortalIty aSsociaTed with PsYchotropic Drug Prescribing in Dementia study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePROSPERO registration\u003c/strong\u003e: CRD42024602796\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGOV.UK [Internet]. 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Mortality in patients with behavioural and psychological symptoms of dementia: a registry-based study. Aging Ment Health. 2021 May 27;25(6):1101\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eHuang TY, Wei YJ, Moyo P, Harris I, Lucas JA, Simoni-Wastila L. Treated Behavioral Symptoms and Mortality in Medicare Beneficiaries in Nursing Homes with Alzheimer\u0026rsquo;s Disease and Related Dementias. J Am Geriatr Soc. 2015 Sept;63(9):1757\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eSu J, Chang C, Wang H, Chen K, Yang Y, Lin C. Antidepressant treatment and mortality risk in patients with dementia and depression: a nationwide population cohort study in Taiwan. Ther Adv CHRONIC Dis. 2019;10. \u003c/li\u003e\n\u003cli\u003eMueller C, Huntley J, Stubbs B, Sommerlad A, Carvalho AF, Perera G, et al. Associations of Neuropsychiatric Symptoms and Antidepressant Prescription with Survival in Alzheimer\u0026rsquo;s Disease. J Am Med Dir Assoc. 2017 Dec 1;18(12):1076\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eMueller C, Perera G, Hayes RD, Shetty H, Stewart R. Associations of acetylcholinesterase inhibitor treatment with reduced mortality in Alzheimer\u0026rsquo;s disease: a retrospective survival analysis. Age Ageing. 2018 Jan 1;47(1):88\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eKazmierski J, Messini-Zachou C, Gkioka M, Tsolaki M. The Impact of a Long-Term Rivastigmine and Donepezil Treatment on All-Cause Mortality in Patients With Alzheimer\u0026rsquo;s Disease. Am J Alzheimers Dis Other Demen. 2018 Sept;33(6):385\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eMcMichael AJ, Zafeiridi E, Ryan M, Cunningham EL, Passmore AP, McGuinness B. Anticholinergic drug use and risk of mortality for people with dementia in Northern Ireland. Aging Ment Health. 2021 Aug;25(8):1475\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eLewis G, Werbeloff N, Hayes JF, Howard R, Osborn DPJ. Diagnosed depression and sociodemographic factors as predictors of mortality in patients with dementia. Br J Psychiatry. 2018;213(2):471\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eBr\u0026auml;nnstr\u0026ouml;m J, Bostr\u0026ouml;m G, Rosendahl E, Nordstr\u0026ouml;m P, Littbrand H, L\u0026ouml;vheim H, et al. Psychotropic drug use and mortality in old people with dementia: investigating sex differences. BMC Pharmacol Toxicol. 2017 May 25;18(1):36. \u003c/li\u003e\n\u003cli\u003eMaust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015 May;72(5):438\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eRichardson K, Savva GM, Boyd PJ, Aldus C, Maidment I, Pakpahan E, et al. Non-benzodiazepine hypnotic use for sleep disturbance in people aged over 55 years living with dementia: a series of cohort studies. Health Technol Assess Winch Engl. 2021 Jan;25(1):1\u0026ndash;202. \u003c/li\u003e\n\u003cli\u003eWatt JA, Gomes T, Bronskill SE, Huang A, Austin PC, Ho JM, et al. Comparative risk of harm associated with trazodone or atypical antipsychotic use in older adults with dementia: a retrospective cohort study. CMAJ Can Med Assoc J J Assoc Medicale Can. 2018 Nov 26;190(47):E1376\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eKollhorst B, Jobski K, Krappweis J, Schink T, Garbe E, Schmedt N. Antidepressants and the risk of death in older patients with depression: A population-based cohort study. PloS One. 2019;14(4):e0215289. \u003c/li\u003e\n\u003cli\u003eBishara D, Perera G, Harwood D, Taylor D, Sauer J, Funnell N, et al. Centrally-acting anticholinergic drugs- associations with mortality, hospitalisation and cognitive decline following dementia diagnosis in people receiving antidepressant and antipsychotic drugs. Aging Ment Health. 2022 Sept;26(9):1747\u0026ndash;55. \u003c/li\u003e\n\u003cli\u003eRichardson K, Loke YK, Fox C, Maidment I, Howard R, Steel N, et al. Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study. BMC Med. 2020 Nov 24;18(1):351. \u003c/li\u003e\n\u003cli\u003eSaarelainen L, Tolppanen AM, Koponen M, Tanskanen A, Tiihonen J, Hartikainen S, et al. Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: A matched cohort study. Int J Geriatr Psychiatry. 2018 Apr;33(4):583\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eSarycheva T, Lavikainen P, Taipale H, Tiihonen J, Tanskanen A, Hartikainen S, et al. Antiepileptic drug use and mortality among community-dwelling persons with Alzheimer disease. Neurology. 2020 May 19;94(20):e2099\u0026ndash;108. \u003c/li\u003e\n\u003cli\u003eConnors MH, Ames D, Boundy K, Clarnette R, Kurrle S, Mander A, et al. Predictors of Mortality in Dementia: The PRIME Study. J Alzheimers Dis JAD. 2016 Apr 12;52(3):967\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eCullum S, Varghese C, Coomarasamy C, Whittington R, Hadfield L, Rajay A, et al. Predictors of mortality in Māori, Pacific Island, and European patients diagnosed with dementia at a New Zealand Memory Service. Int J Geriatr Psychiatry. 2020;35(5):516\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eToshie M, Mizukami K, Matsuoka T, Ogawa N, Kensaka T, Taniguchi C, et al. Effects of drug treatment on the surviral-time in patients with dementia. Jpn J Geriatr. 2019;56(2):171\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eErdal A, Flo E, Aarsland D, Ballard C, Slettebo DD, Husebo BS. Efficacy and Safety of Analgesic Treatment for Depression in People with Advanced Dementia: Randomised, Multicentre, Double-Blind, Placebo-Controlled Trial (DEP.PAIN.DEM). Drugs Aging. 2018 June;35(6):545\u0026ndash;58. \u003c/li\u003e\n\u003cli\u003eRoach P, Lovell MR, Macfarlane S. Dying with behavioral and psychological symptoms of dementia in Australian nursing homes: a retrospective case-control study. Front Psychiatry [Internet]. 2023;14. Available from: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85161082351\u0026amp;doi=10.3389%2ffpsyt.2023.1091771\u0026amp;partnerID=40\u0026amp;md5=62665ad87bb09363847ebf3f8ba6e199\u003c/li\u003e\n\u003cli\u003eBarrett B, Schultz SK, Luther SL, Friedman Y, Cowan L, Bulat T. Mortality and Associated Risk Factors in Community-Dwelling Persons With Early Dementia. Alzheimer Dis Assoc Disord. 2020 Mar;34(1):40\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eMo M, Abzhandadze T, Hoang MT, Sacuiu S, Jurado PG, Pereira JB, et al. Antidepressant use and cognitive decline in patients with dementia: a national cohort study. BMC Med. 2025 Feb 25;23(1):82. \u003c/li\u003e\n\u003cli\u003eBakken MS, Engeland A, Enges\u0026aelig;ter LB, Ranhoff AH, Hunskaar S, Ruths S. Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry. Age Ageing. 2013 July;42(4):514\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eZakarias JK, N\u0026oslash;rgaard A, Jensen-Dahm C, Gasse C, Laursen TM, Palm H, et al. Risk of hospitalization and hip fracture associated with psychotropic polypharmacy in patients with dementia: A nationwide register-based study. Int J Geriatr Psychiatry. 2021;36(11):1691\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eRozing MP, Wium-Andersen MK, Wium-Andersen IK, J\u0026oslash;rgensen TSH, J\u0026oslash;rgensen MB, Osler M. Use of hypnotic-sedative medication and risk of falls and fractures in adults: A self-controlled case series study. Acta Psychiatr Scand. 2023;148(5):394\u0026ndash;404. \u003c/li\u003e\n\u003cli\u003eAhmad G, McManus S, Cooper C, Hatch SL, Das-Munshi J. Prevalence of common mental disorders and treatment receipt for people from ethnic minority backgrounds in England: repeated cross-sectional surveys of the general population in 2007 and 2014. Br J Psychiatry J Ment Sci. 2022 Sept;221(3):520\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eLarsen AJ, Teobaldi G, Espinoza Jeraldo RI, Falkai P, Cooper C. Effectiveness of pharmacological and non-pharmacological interventions for treatment-resistant depression in older patients: a systematic review and meta-analysis. BMJ Ment Health. 2025 Mar;28(1):e301324. \u003c/li\u003e\n\u003cli\u003eRichards M, Bell G, Ei Baou C, Saunders R, Buckman J, Charlesworth G, et al. Effectiveness of primary care psychological therapy services for the treatment of depression and anxiety in people living with dementia: evidence from national healthcare records in England. EClinical Med. 2022 Sept 26; \u003c/li\u003e\n\u003cli\u003eBell G, El Baou C, Saunders R, Buckman JE, Charlesworth G, Richards M, et al. Predictors of primary care psychological therapy outcomes for depression and anxiety in people living with dementia: evidence from national healthcare records in England. Br J Psychiatry. 2024;224(6):205\u0026ndash;12. \u003c/li\u003e\n\u003cli\u003eWattmo C, Londos E, Minthon L. Cholinesterase inhibitors do not alter the length of stay in nursing homes among patients with Alzheimer\u0026rsquo;s disease: a prospective, observational study of factors affecting survival time from admission to death. BMC Neurol. 2016 Aug 31;16(1):156. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Study characteristics and results for Randomised Controlled Trials\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSetting, country\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal sample size\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDementia type, indication\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex (f), Ethnicity (white)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n, %)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention arm\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment duration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow up time for mortality outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMortality rate intervention vs control\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eBanerjee (2021)(28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e26 NHS clinical centres, UK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eAD,\u003c/p\u003e\n \u003cp\u003eagitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e135 (66.2%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMirtazapine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e12 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e16 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e7/102 (6.86%) vs 1/102 (0.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eFisher\u0026rsquo;s exact test p=0\u0026middot;065\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eBanerjee (2011)(29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e9 NHS clinical centres, England\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eAD, depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e221 (67.8%), 303 (92.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eSertraline\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e39 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e39 weeks\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e5/107 (4.67%), 5/108 (4.63%) vs 5/111 (4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eND\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMirtazapine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eErdal (2018) (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e47 nursing homes, Norway\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eAll cause dementia, depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e122 (75.3%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eParacetamol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e36\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e37\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e13 weeks\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e13 weeks\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eNR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003ePearson x\u003csup\u003e2\u003c/sup\u003e test; p = 0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eBuprenorphine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003ePlacebo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" valign=\"top\" style=\"width: 1026px;\"\u003e\n \u003cp\u003e\u003cem\u003eUK\u003c/em\u003e United Kingdom; \u003cem\u003eAD\u0026nbsp;\u003c/em\u003eAlzheimer\u0026rsquo;s disease;\u003cem\u003e\u0026nbsp;ND\u003c/em\u003e not done; NHS, National Health Service; \u003cem\u003eNR\u003c/em\u003e not reported;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 Study characteristics and results for case control studies, investigating odds of mortality associated with non-antipsychotic prescribing in populations with dementia\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"987\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDementia sample population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow up time\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk of mortality associated with psychotropic prescribing (adjusted)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCovariates adjusted for\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eJohnell (2017)\u003c/p\u003e\n \u003cp\u003eSweden (26)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePatients from all inpatient and specialized outpatient care in Sweden; aged 65+ with dementia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDied in 2011 (except\u003c/p\u003e\n \u003cp\u003esuicides \u0026amp; undetermined deaths)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e10,341\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAlive end of 2011; matched by age, sex \u0026amp; case event day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e24,880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1 year\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eAntidepressant aOR: 1.14; [CI] 1.08\u0026ndash;1.21\u003c/p\u003e\n \u003cp\u003eAnxiolytics aOR: 1.33; [CI] 1.25\u0026ndash;1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eEducation level, inpatient days, Charlson co-morbidity index, co-prescribing (including antipsychotics)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eRoach (2023) (54)\u003c/p\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eCare home residents referred to Dementia Support Australia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDied November 2015-16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAlive; sex matched\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eRegular benzodiazepine use: OR 5.62; [CI] 2.17-14.48, p = 0.0004\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBuprenorphine: OR 2.32 [CI]0.98\u0026ndash;5.49\u003c/p\u003e\n \u003cp\u003eAD: OR 1.58 [CI]0.68\u0026ndash;3.66\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMood stabilisers: OR 0.25 [CI]0.81\u0026ndash;0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" valign=\"top\" style=\"width: 987px;\"\u003e\n \u003cp\u003e\u003cem\u003en\u0026nbsp;\u003c/em\u003esample size; \u003cem\u003eAD\u003c/em\u003e antidepressant; \u003cem\u003eaOR\u003c/em\u003e adjusted odds ratio;\u003cem\u003e\u0026nbsp;ns\u003c/em\u003e not significant; \u003cem\u003eOR\u0026nbsp;\u003c/em\u003eodds ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3 Study characteristics and results for cohort studies\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1058\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDementia sample population\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale (n,%); White majority ethnicity (n,%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedication (category *)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow up, mortality outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMortality risk (adjusted);\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eaHR (CI) unless stated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCovariates adjusted for\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBarrett (2020)(55)\u003c/p\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eCommunity dwelling veterans aged 60+ with mild dementia from memory clinic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e14 (9.8%), 134 (94.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e(1) anticholinergic (mixed)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e(1) =3.30, P=0.07\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e(2) sedatives (mixed)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e (1) =0.13, P= 0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBishara (2022) (46)\u003c/p\u003e\n \u003cp\u003eUK\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients aged 50+; first dementia diagnosis, London 2ndry psychiatric services 2008 \u0026ndash; 17; any antidepressant at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4,380\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2,847 (65%), 3,364 (76.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e(1) no cholinergic burden (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3 years (SD +/- 2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e(3) vs (2/3): 0.88 (0.79-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, ethnicity, marital status, MMSE, deprivation, antipsychotics, HoNOS scores, AChEI, cardiovascular disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e(2) Intermediate burden (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e(2) vs (1): 0.97 (0.84-1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e(3) High burden (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e(3) vs (1): 0.86 (0.72-1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBr\u0026auml;nnstr\u0026ouml;m (2017) (41)\u003c/p\u003e\n \u003cp\u003eFinland and Sweden\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eParticipants with dementia from: epidemiological study inviting residents aged 85+, in selected municipalities; observational study and 2 RCTs in Sweden: nursing home residents, age \u0026ge; 65 years, ADLs dependent, MMSE \u0026ge; 10\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e769 (74.2%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.96 (0.78-1.17), p=0.05; men: 0.61 (0.40\u0026ndash;0.92); women: 1.09 (0.87\u0026ndash;1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, comorbidities, prescribed drugs, Barthel ADL Index, BMI, GDS-15, MMSE\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines (HAS)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.72 (0.54-0.96), p=0.96; men: 0.81 (0.45-1.45); women: 0.73 (0.53-1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBr\u0026auml;nsvik (2021) (33)\u003c/p\u003e\n \u003cp\u003eSweden\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eIndividuals with all cause dementia who were registered in the BPSD registry 2010\u0026ndash;13 (national registry to support nursing home management of BPSD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11,448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e7485 (65.4%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAnalgesics (OA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003emean (SD) 250.3 (191.6) days,\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.07(0.98 \u0026ndash;1.17), p=0.14**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, dementia diagnosis, medication, previous myocardial infarction, hip fracture and stroke.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAntiepileptics(MA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.92 (0.75-1.12) p=0.40**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAnxiolytics (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.90 (0.81-1.01), p=0.07**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHypnotics (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.99 (0.88-1.11), p=0.89**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.81(0.74-0.89), p \u0026lt;.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eChen (2023)\u003c/p\u003e\n \u003cp\u003eUK (22)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients with dementia admitted to one UK hospital with first covid infection 23.3.20 \u0026ndash; 10.4.22 formed the \u0026ldquo;exposure cohort\u0026rdquo;; compared to a control cohort without covid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1,490\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e890 (59.7%), 1,190(79.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepine (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e239.4 (237.0) days\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e3.00 (1.28-7.03), p\u0026lt;0.5***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, marital status, ethnicity, physical comorbidity, psychotropic co-prescribing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAntidepressant (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.16 (0.54-2.51)***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eOpioid drugs (OA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e2.10 (0.88-4.95)***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAntiepileptic (MA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.49 (0.62-3.60)***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eConnors (2016)\u003c/p\u003e\n \u003cp\u003eAustralia (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients from nine memory clinics with all cause dementia, living in the community receiving \u0026lt;40 hours a week nursing care.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e779\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e371 (47.6%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e8 years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.91 (0.66\u0026ndash;1.26), p = 0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, marital status, dementia type, cognition, dementia severity, NPS, number drugs, antipsychotics\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eCullum (2020)\u003c/p\u003e\n \u003cp\u003eNew Zealand (51)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients with all cause dementia recruited from South Auckland memory service in, 2013-17\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e475\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e271 (57.05%), NR\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eTo death/ last contact, up to 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.89 (0.48-1.64), p = 0.699\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, ethnicity, dementia type, cognitive score, comorbidity, AChEI, antipsychotics\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eEnache (2016)\u003c/p\u003e\n \u003cp\u003eSweden (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eMemory clinic patients with all cause dementia, from SveDem registered 2007-2013 linked to the prescribed drug register.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e20,050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11,642 (58.1%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eOne year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.92 (0.86-0.99), p\u0026lt;0.05.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, number of medications, MMSE, living in home or nursing home, dementia subtype.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eFeresh-tehnejad (2018)\u003c/p\u003e\n \u003cp\u003eSweden (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients from the SveDem; registered 2007\u0026ndash;2015 from memory clinics and primary care units: with DLB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1,110\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e430 (38.7%), NR\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMedian survival:\u003c/p\u003e\n \u003cp\u003e4.0 years\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.85 (0.67-1.09)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, number of medications, MMSE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients from the SveDem; registered 2007\u0026ndash;2015 from memory clinics and primary care units: with PDD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e275\u003c/p\u003e\n \u003cp\u003e(36.0%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMedian survival:\u003c/p\u003e\n \u003cp\u003e4.1 years\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.76 (1.28\u0026ndash;2.42), p = 0.001.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eHuang (2015)\u003c/p\u003e\n \u003cp\u003eUSA (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e2006-2009 Medicare data of nursing home residents with Alzheimer\u0026rsquo;s disease and related dementias\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1,661\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1176 (70.8%), 1425 (85.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.82 (0.70\u0026ndash;0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, race, ethnicity, region, income, NPS, comorbidity,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003efunction, hospital or nursing facility stay, co-medications\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eHuybrechts (2011)\u003c/p\u003e\n \u003cp\u003eCanada (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eIndividuals aged 65+, admitted to British Columbia nursing home 1/1/1996 \u0026ndash; 31/3/2006.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4,043\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNR for the subgroup with dementia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD vs antipsychotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e180 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eRR 1.22 (0.88\u0026ndash;1.70)*****\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, year, comorbidities, prior medication use.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines vs antipsychotics (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eRR 1.21 (0.87\u0026ndash;1.68)*****\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eKazmierski (2018)\u003c/p\u003e\n \u003cp\u003eGreece\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients with Alzheimer\u0026rsquo;s disease/ related dementia from Memory Clinic / day centres, taking AChEI\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1171\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e725 (62%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.90 (0.58-1.41), p= 0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAnxiolytics (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.59 (0.29-1.23), p=0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eKollhorst (2019)\u003c/p\u003e\n \u003cp\u003eGermany (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eIndividuals were AD initiators (2005\u0026ndash;2015), aged 65+, had 1-year continuous insurance and \u0026ge;1 hospital or outpatient depression diagnosis and dementia.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e50,511\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNR for the subgroup with dementia\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eEscitalopram (AD)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMedian: 51\u0026ndash;233 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.96 (0.85\u0026ndash;1.08)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"12\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, comorbidities, frailty indicators, and co-medications.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eSertraline (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.99 (0.91\u0026ndash;1.07)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eFluoxetine (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.98 (0.82\u0026ndash;1.18)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eParoxetine (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.89 (0.73\u0026ndash;1.08)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eVenlafaxine (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.95 (0.83\u0026ndash;1.09)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eDuloxetine (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.83 (0.69\u0026ndash;0.99)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAmitriptyline (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.15 (1.05\u0026ndash;1.25)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eDoxepin (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.85 (0.72\u0026ndash;0.99)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eTrimipramine (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.77 (0.63\u0026ndash;0.95)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eOpipramol (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.87 (0.76\u0026ndash;1.00)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eMirtazapine (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.97 (0.92\u0026ndash;1.02)****\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eSt. Johns Wort (AD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.55 (0.46\u0026ndash;0.67)**** \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eLewis (2018)\u003c/p\u003e\n \u003cp\u003eUK (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eSecondary mental healthcare patients diagnosed with dementia, Camden and Islington NHS trust London. 2008-2016.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3374\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2045 (61%), white 2693 (79.82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003emean 3.22 (SD 2.16) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.15 (0.99-1.33), \u003cem\u003ep\u003c/em\u003e=0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, ethnicity, marital status, IMD tertiles, MMSE, depression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMaust (2015)\u003c/p\u003e\n \u003cp\u003eUSA (42)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eVeterans\u0026rsquo; health registries data: patients aged 65+ with dementia and \u0026ge;1 inpatient or outpatient episode, 1998-09.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e46,008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1,150 (2.5%), 32,707 (71.1%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e180 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eaRD: 0.6 (0.3-0.9), p\u0026lt;.01\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, marital status, mental conditions, medication, healthcare use, comorbidities\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eValproic acid \u0026nbsp;(MA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eaRD: 4.1 (-1.0-9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMcMichael (2020)\u003c/p\u003e\n \u003cp\u003eUK (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eAll patients in Northern Ireland that received antidementia medication (cholinesterase inhibitors and memantine) 2010-2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e25418\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e16537 (65%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHypnotics and anxiolytics (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e7 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.08 (0.98\u0026ndash;1.19)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, marital status, deprivation measure, urban/rural classification, comorbidity, medications.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.08 (0.99\u0026ndash;1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMcMichael (2021)\u003c/p\u003e\n \u003cp\u003eUK (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.12 (0.94\u0026ndash;1.33)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, marital status, urban/rural, area deprivation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMostafaei (2023)\u003c/p\u003e\n \u003cp\u003eSweden (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients diagnosed with dementia in the SveDem registry between 2007\u0026ndash;2018; aged 65+ at diagnosis.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e28023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e16273 (58.07%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMedian follow-up time: 1053 days for survivors, 1125 days for deceased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eElastic-net logistic regression: importance value 3%. 0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, MMSE, BMI, comorbidity, dementia type, comorbidities, dementia medications, number of medications, referral to diagnosis time, physiotherapist assessment, residence, alcohol diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMueller (2017)\u003c/p\u003e\n \u003cp\u003eUK (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eMild Alzheimer\u0026rsquo;s disease diagnosed at South London outpatient services 2006-16\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5473\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3504 (64.02%), 4312 (78.78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMean 3.5 years SD 2.4 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.25 (1.06-1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, ethnicity, marital status, deprivation, cognitive scores, HoNOS-65+ subscales, comorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMueller (2018)\u003c/p\u003e\n \u003cp\u003eUK (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eAged 65+, Alzheimer\u0026rsquo;s disease from South London outpatient services 2008-12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1642 (66.6%), 2014 (81.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMean 3.7 SD\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.7 years.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.16 (0.99\u0026ndash;1.37)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.28 (1.02\u0026ndash;1.62), p \u0026lt; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eRichardson (2021) (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eWHELD cluster RCT, residents with dementia in 69 care homes in England (2013-15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e926\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e659 (71%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e877 (95%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eZ-drugs (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e9 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eOdds Ratio (death in z-drug vs non-users): 0.66 (0.38 to 1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, ethnicity, marital status, CDR, Abbey Pain Scale score, comorbidity and co-medication use\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eRichardson (2020),\u003c/p\u003e\n \u003cp\u003eUK (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePeople diagnosed with dementia between January 2000-March 2016, aged 55+ from CPRD data linked to HES data in England. Those newly prescribed z-drugs and non-sedative-users with sleep disturbance.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5356\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3232 (60.3%), 4611 (86%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eZ-drug vs non-users with sleep deprivation (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eMedian (IQR) of 3.5\u003c/p\u003e\n \u003cp\u003e(3.0\u0026ndash;10.3) months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.38 (1.14-1.66)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, health behaviours, immunisations, dementia subtype, sleep disturbance severity, comorbidities, medical history, concurrent medication use.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eZ-drugs vs matched controls with proximal GP consultation (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.08 (0.94\u0026ndash;1.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eZ-drugs vs benzodiazepines (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.73 (0.64\u0026ndash;0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eSaarelainen (2018)\u003c/p\u003e\n \u003cp\u003eFinland (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"10\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eMEDALZ cohort of\u003c/p\u003e\n \u003cp\u003ecommunity dwelling people diagnosed with Alzheimer\u0026rsquo;s disease 2005-11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e31,140 (users/ matched non-users\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e19,592 (62.9%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e180 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.59 (1.35‐1.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eComorbidity, socio-economic status, prior opioid, antidepressant, antipsychotic, use.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eZ-drugs (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.06 (0.83‐1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines and related drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.40 (1.25‐1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eSarycheva (2020)\u003c/p\u003e\n \u003cp\u003eFinland (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11,276 (users/ matched non-users)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAnti-epileptic (MA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3 years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.16 (1.05\u0026ndash;1.28)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, medication use, medical history, psychiatric history, substance abuse.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePregabalin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.51 (0.42\u0026ndash;0.63)\u003csup\u003e%\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eCarbamazepine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.91 (0.67\u0026ndash;1.25)\u003csup\u003e\u0026nbsp;%\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eClonazepam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.44 (0.26\u0026ndash;0.76)\u003csup\u003e\u0026nbsp;%\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eOxcarbazepine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.93 (0.65\u0026ndash;1.32)\u003csup\u003e\u0026nbsp;%\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eGabapentin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.40 (0.26\u0026ndash;0.62)\u003csup\u003e\u0026nbsp;%\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePhenytoin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.63 (0.37\u0026ndash;1.07)\u003csup\u003e%\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eSu (2019) (35)\u003c/p\u003e\n \u003cp\u003eTaiwan\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients aged 60+, diagnosed with dementia 2000-11, then diagnosed with depression\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e44,116\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e14,218 (54.92%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD (lower dose)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eUntil 2013\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.98 (0.93-1.03), p = 0.33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, urbanization, income, date\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD (higher dose)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.65 (0.62-0.69), p\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eTolppanen (2016)\u003c/p\u003e\n \u003cp\u003eFinland (24)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eMEDALZ cohort of\u003c/p\u003e\n \u003cp\u003ecommunity dwelling people with Alzheimer\u0026rsquo;s disease 2005-2011, who sustained a first hip fracture in observation period\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4,851\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1.3 years (range 1 day-7.7 years)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.97 (0.89-1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eOccupational social class\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepines (HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.06 (0.98-1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eOpioids (OA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.29 (1.19-1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eAntiepileptic (MA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.12 (0.99-1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eToshie (2019) (52)\u003c/p\u003e\n \u003cp\u003eJapan\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePatients hospitalized in Toyohashi (2012\u0026ndash;16), post-mortem dementia diagnosis, available medication data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e44 (57.9%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eBenzodiazepine \u0026nbsp;(HAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eAdmission to death\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.07 (0.56 -2.03, p=0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.00 (0.57-1.75), p=0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eWatt (2018)\u003c/p\u003e\n \u003cp\u003eCanada (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eAdults with dementia, aged 66+ living in long term care, with new prescription of trazadone or AA, 2009-15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6588 trazadone2875 AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e6502(68.7%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eTrazadone (AD) vs AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e90 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.75 (0.66-0.85)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, sex, function, health care use, medication use, medical history, performance scales.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eWattmo (2016) (64)\u003c/p\u003e\n \u003cp\u003eSweden\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePeople with Alzheimer\u0026rsquo;s disease recruited in 1997 for open AChEI study; who died while living in a NH; MMSE 10-26 at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e161 (73%), NR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eUntil 31.12.14\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eMD: \u0026minus;1.03 (\u0026minus;1.91-\u0026minus;0.15); p =0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eSex, living status, antihypertensive/ cardiac therapy, ADL at nursing home placement\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*\u003cem\u003eCategories in which medication analysed in this paper: AD: antidepressants; HAS: Hypnotics, Anxiolytics, Sedatives; MA:\u0026nbsp;\u003c/em\u003e\u003cem\u003eMood stabilisers/ antiepileptics; Mixed; OA: Opioids/analgesics; see Supplementary file D for details of all medications included **\u003c/em\u003e Association between BPSD and mortality adjusted for drug of interest; *** aHR (case-control comparing exposure/ non-exposure cohorts) = 4.44, [CI] 3.13\u0026ndash;6.30; additional risk associated with drug of interest shown: **** risk compared with citalopram; *****Noncancer related mortality; \u003csup\u003e%\u003c/sup\u003e: relative to valproic acid\u003c/p\u003e\n\u003cp\u003eAA: Atypical Antipsychotics; AChEI : anticholinesterase inhibitors; aRD: Associated Risk Difference; \u0026nbsp;aHR: Adjusted Hazard Ratio; CI: Confidence Interval; DLB: Dementia Lewy Body; HoNOS : Health of the National Outcome Scales; IMD: Index of Multiple Deprivation; MD: Mean difference in years lived; MMSE: Mini Mental State Examination; NPS: Neuropsychiatric Symptoms; PDD: Parkinson\u0026rsquo;s Disease Dementia; RR: Relative Risk\u003c/p\u003e\n\u003cp\u003eNote: all numerical values shown to 2 decimal places\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9539696/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9539696/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eAntipsychotics, prescribed to manage behavioural and distress symptoms in dementia, are associated with increased mortality, so are often substituted with other medications. This review examines mortality risks associated with these alternatives.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod: \u003c/strong\u003eWe searched four electronic databases (January 2010 - October 2024), including randomised controlled trials, cohort and case-control studies involving people with dementia prescribed psychotropic medications (e.g., antidepressants, anxiolytics, mood stabilisers, sedatives, analgesics) other than antipsychotics. We assessed risk of bias using Cochrane Risk of Bias 2 and Newcastle-Ottawa Scale, and rated evidence certainty using GRADE criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThirty-six studies met inclusion criteria, most examining antidepressants (k=25). Only three were rated as being at low risk of bias. Low study quality and heterogeneity precluded meta-analyses. We found weak evidence of a trend in those prescribed antidepressants towards greater mortality risk in one high quality RCT, and lower risk in naturalistic cohort studies, relative to control conditions. Hypnotic, sedative or anxiolytic prescribing was not associated with greater all-cause mortality, relative to control conditions. Evidence for mood stabilisers/antiepileptics and opioids/analgesics was limited and inconsistent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eFindings of a lack of clear association between prescribing and mortality should not be interpreted as evidence of safety.\u003cstrong\u003e \u0026nbsp;\u003c/strong\u003eFuture studies should examine impact of the drug types, dosages, treatment duration and adherence, to clarify potential within-class variation in mortality risk. Given the paucity of RCT evidence and practical challenges of powering trials for mortality, robust real-world studies are a priority. Pragmatic or registry-based randomised evaluations of mortality risks associated with treatment strategies may also be feasible.\u003c/p\u003e","manuscriptTitle":"Mortality risk associated with psychotropic medications frequently substituted for antipsychotics to manage behaviours that challenge in people with dementia: a systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 13:13:44","doi":"10.21203/rs.3.rs-9539696/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec14028f-ac57-4090-b189-464fa51aead6","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-28T13:13:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 13:13:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9539696","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9539696","identity":"rs-9539696","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}