TITLE: Long-term Use of Benzodiazepines: A Review of the Clinical Effectiveness and Safety

TITLE: Long-term Use of Benzodiazepines: A Review of the Clinical Effectiveness and Safety DATE: 12 August 2015 CONTEXT AND POLICY ISSUES Benzodiazepines (BZDs) are gamma-aminobutyric acid (GABA) receptor agonists with a broad range of activities including hypnotic/sedative, anxiolytic, anti-spasmodic and anti-convulsant effects. Present on the World Health Organisation s list of essential medicines, benzodiazepines are a class of drugs with a broad therapeutic use that includes treatment of alcohol/amphetamine withdrawal, anaesthesia, sedation, anxiolysis, behavioural disturbance, epilepsy, insomnia, palliative care, and muscle spasm. 1 This class of psychoactive drugs is commonly subclassified by its pharmacokinetic properties into: short- (e.g., midazolam, triazolam), intermediate- (e.g., alprazolam, lorazepam, temazepam) and long-acting agents (e.g., diazepam, clobazam, clonazepam, clorazepate, chlordiazepoxide, flurazepam). Short and intermediate-acting agents are typically used as hypnotics, while long-acting agents are more commonly used as anxiolytics, anti-spasmodic and anticonvulsants. 2 Benzodiazepines remain widely prescribed in most industrialized countries; 2-4 yet questions have not been resolved within the medical community regarding its risk-benefit profile. Concerns relate to its unfavorable side-effect profile, their propensity for dependence and their potential for abuse. Studies have found an association between benzodiazepines and cognitive and psychomotor impairment. 5 Paradoxical excitement can have further forensic implications. Specifically in the elderly, long-acting agents are particularly problematic given age-related reduction in metabolic function and the increased risks of confusion, depression, falls and ataxia. 6 Although the abuse potential for benzodiazepines is more difficult to assess, a black market does exist in which prescriptions are diverted to users who are consuming them not under the care of a healthcare professional. Overdose of benzodiazepines can induce respiratory depression and coma, and are a significant cause of mortality. 2 Prescribing guidelines therefore discourage the prolonged use of benzodiazepines to minimize the risk of dependency and withdrawal symptoms. 7 Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

Despite this, long-term use is common and the long-term efficacy and safety remains poorly documented. The purpose of this review is therefore to assess the available evidence on longterm use of benzodiazepines in adult patients in terms of their clinical effectiveness and safety when compared to short-term benzodiazepine use. RESEARCH QUESTIONS 1. What is the clinical effectiveness of long-term versus short-term use of benzodiazepines? 2. What is the clinical evidence regarding the safety of long-term use of benzodiazepines? KEY FINDINGS In terms of safety, four systematic reviews were identified that addressed the safety of long-term administration of benzodiazepines compared to either placebo or no benzodiazepine use. Of these, a consistent association was found between long-term use of benzodiazepines and an increased risk of dementia when compared to non-users. There remains little evidence pertaining to other safety outcomes. No studies were identified that evaluated the efficacy and safety of long-term versus short-term benzodiazepines use. METHODS Literature Search Strategy A limited literature search was conducted on key resources including Ovid Medline, Pubmed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and June 30, 2015. Selection Criteria and Methods One reviewer screened the literature search results to identify relevant publications, including: health technology assessments (HTAs); systematic reviews (SRs) and meta-analyses (MA); and randomized controlled trials (RCTs). The initial screen was based on title and abstract. A second reviewer completed full-text screening. At both stages of screening, studies considered for inclusion were based on the selection criteria presented in Table 1. Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Adults taking any benzodiazepines long-term for any indication Long-term benzodiazepine treatment (defined as treatment of more than 5 days; including other definitions of long term, e.g., 30 days) Question 1: Short-term benzodiazepine (5 days or less) Question 2: Short-term benzodiazepine or no comparator Clinical effectiveness Safety (e.g., adverse events, cognitive impairment) Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials Long-term Use of Benzodiazepines 2

Exclusion Criteria Articles were excluded if there were a duplicate report of the same study; if they were already included in a selected SR or HTA; if they were published prior to 2010; or if they did not meet the specified inclusion criteria. Critical Appraisal of Individual Studies SRs were appraised using the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist. 8 Items considered in the AMSTAR checklist include: a priori design of the review; duplicate independent reviewers; a priori defined eligibility criteria; comprehensive search of information sources; transparent reporting of study selection; clear presentation of study characteristics; assessment of studies quality; scientifically-sound interpretation of the results; appropriate methods to combine data from studies; assessment of publication bias; and reporting of funding sources. 8 RCTs were appraised using the Downs and Black checklist. 9 Concepts evaluated within this 27- item checklist included: reporting, external validity, internal validity (separated into bias and confounding), and power. 9 In conducting the critical appraisal, an overall numeric score was not calculated for each study. Instead, the selected instrument helped identify strengths and limitations that were subsequently reviewed narratively for the included publications. SUMMARY OF EVIDENCE Quantity of Research Available A total of 175 citations were identified from the literature search. Following screening of titles and abstracts, six potentially relevant reports were selected for full-text review. Three publications were found to satisfy the full inclusion criteria and, alongside the inclusion of one report from grey literature sources, a total of four SRs were included as part of this report. 1,10-12 No clinical trial or HTA report were identified from the literature search that met the complete inclusion criteria. Appendix 1 presents the PRISMA flowchart 13 detailing the study selection. Additional references of potential interest that do not meet the selection criteria are provided in Appendix 2. Summary of Study Characteristics The table summarizing study characteristics is provided in Appendix 3. Four SRs were identified, published by authors originating from UK, 1,12 France 10 and China 11 with the latest search conducted in 2014.Individual trials identified within these SRs were conducted in numerous jurisdictions. One review only included RCTs 12 while the remainder extended the inclusion to observational studies. Sample size of individual studies varied from 403 to 34,158 in the observational studies and 12 to 93 in the RCTs. Long-term Use of Benzodiazepines 3

All four SRs were interested in evaluating the safety of long-term benzodiazepine administration compared to placebo. The definition of long-term use was not clear in any of the reviews. The majority of these reviews further had a broad scope by covering any indication, except in one that was specifically interested in patients with schizophrenia. 12 In all reviews, the intervention of interest was any agent within the benzodiazepine drug class. In some studies, the analysis was separated into categories of utilization such as: ever use, current use, recent use and/or past/former use. 10,11 Although most, if not all of the trials were compared to non-users of benzodiazepines 10,11 or placebo, 12 this was not clear in one of the SRs. 1 No reviews were found that have compared the safety and efficacy of long-term versus short-term benzodiazepine treatment. One SR broadly addressed all safety outcomes 12 while three were focused on specific outcomes: two on dementia 10,11 and one on mortality. 1 The review that addressed all adverse events were specific to patients on benzodiazepines for the treatment of schizophrenia. 12 This review included RCTs only, with the average age ranging from 33 to 40 years. Trial duration was shorter as the study outcomes were assessed at week 1 to week 8 with the exception of one study that assessed relapse by following patients up to three years. The SRs on dementia outcomes included observational study designs, with a maximum follow-up duration between 3 to 25 years. 10,11 The inclusion criteria of some studies required patients to be at least 45 years of age. One of these SR noted that the mean patient age ranged between 61.2 to 78.2 years old. 11 Finally the study on mortality outcomes had similarly a broad follow-up duration ranging one to 20 years. Diverse populations were captured in the included observational studies: sampling could be condition specific (e.g., dialysis) or based on a general population/community cohort. As such, the age range of these studies varied considerably. One review had the intention of employing meta-analysis to pool data from individual studies to assess the association between benzodiazepine use and dementia. 11 The remaining three SRs provided a narrative synthesis. Summary of Critical Appraisal A summary of the critical appraisal is presented in Appendix 4. The SRs were generally conducted with poor quality. With the exception that all studies disclosed their potential conflict of interest, the rigour to which these reviews were conducted was uncertain on many counts. None of the studies explored grey literature and two studies searched a single database. 1,10 Most trials did provide the date of the last search 10-12 but few provided a start date. 10 Furthermore, two of the reviews did not report several key methodological details such as the inclusion criteria for study selection, whether screening was done independently and in duplicate, and how data were extracted. 1,10 A list of excluded studies was not provided although the majority of the reviews did provide a list of their included studies alongside the study characteristics. 1,10,11 Publication bias was rarely considered, and in the single case where it was mentioned, 11 the analysis was inappropriately conducted. The Cochrane recommendation is that publication bias should only be assessed when there are more than ten trials identified, although this was not the case in that review. 11 Critical appraisal of the included studies was performed in the two reviews that addressed the Long-term Use of Benzodiazepines 4

association between benzodiazepine and dementia. 10,11 Billioti de Gage et al. 10 and Zhong et al. 11 came to similar conclusions and were consistent in the evaluation of studies that they shared in common. Overall, most of their included studies were deemed to be conducted of high quality. Billioti de Gage et al. 10 also addressed protopathic bias (i.e., reverse causality). Amongst their ten included trials, five were considered likely at risk of protopathic bias (often due to short follow-up duration) while two were found to have a possible risk. One study addressed the quality of trial reporting by following the CONSORT guidelines although critical appraisal of the potential risk of bias was not conducted. 12 In the review that conducted a metaanalysis to pool the data from the observational trials, a random-effects model was selected to account for study heterogeneity. 11 Summary of Findings Main study findings and author conclusions are provided in Appendix 5. Clinical Efficacy No studies were identified that compared the clinical efficacy between long-term and short-term use of benzodiazepines. Safety The four SRs addressed the safety of long-term administration of benzodiazepine compared to placebo or non-users. Of these, one broadly addressed any adverse effects while three were focused on specific outcomes: two on dementia and one on mortality. Sim et al. 12 reviewed the safety of benzodiazepines, compared to placebo or antipsychotics, for the treatment of schizophrenia. Seven RCTs were identified that compared either the safety and/or efficacy of long-term benzodiazepine use to placebo. Specific to the adverse events, two studies reported that patients receiving benzodiazepine experienced significantly higher rates of treatment-emergent side effects than patients on placebo. Adverse events common to both arms include gastrointestinal problems, headaches, irritability, movement disorders and autonomic side effects. In general, sedation was reported more frequently in the benzodiazepine arms than the placebo arms. The reviews on specific harm outcomes had more flexible inclusion criteria by permitting observational studies. The two reviews on dementia were consistent as they found an association between long-term use of benzodiazepines and an increased risk of dementia. One review took a narrative approach and found that eight out of their ten identified observational studies showed a statistically increased risk of dementia. 10 Amongst these ten observational trials, six were identified by the second SR and were pooled by meta-analytic techniques. 11 The pooled adjusted risk ratio found an increased risk of dementia in ever users (risk ratio [RR] 1.49, 95% confidence interval [CI]: 1.30 to 1.72), recent users (RR 1.55, 95% CI: 1.31 to 1.83) and past users (RR 1.55, 95% CI: 1.17 to 2.03) when compared to never users of benzodiazepines. It is unclear how the review defined ever use, recent users and past users. A significant dose-response association was noted between benzodiazepine use and dementia in which, for every additional 20 defined daily doses per year, the risk of dementia increased by 22% (RR 1.22, 95% CI: 1.18 to 1.25). The SR on mortality produced mixed findings and noted that there were considerable methodological flaws within each observational study that limits its interpretation. Long-term Use of Benzodiazepines 5

Limitations The clinical evidence identified in this review consisted of four SRs. These reviews addressed specific outcomes (e.g. dementia or mortality) and specific patient populations (e.g. schizophrenia) so the generalizability to other populations or other safety concerns remains unknown. This review primarily found evidence on the safety of long-term administration of benzodiazepines, however long-term was not well defined within the identified reviews. Although RCTs are considered the highest quality of evidence in the evidence hierarchy, most trials are not powered to detect safety issues. The reporting of harm data in this review came mostly from systematic reviews of observational studies. However, it is important to note that observational studies are unable to prove causality and are limited as they can only demonstrate associations between long-term benzodiazepine use and adverse events. As such, a conundrum exists between feasibility and validity. Ideally, RCTs would be preferred as they can demonstrate causality but, given the low incidence for adverse events, a large sample may be required to have sufficient power. A larger sample size can be more feasibly obtained from observational studies although its interpretations are limited to association and not causality. No RCTs were identified that have compared the efficacy between long-term and short-term administration of benzodiazepine. Most of the evidence on safety is focused on dementia and more research may be warranted to address other harm outcomes. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING This review aimed to address the efficacy and safety of long-term use of benzodiazepines in adults. From the literature search, four SRs were identified that compared long-term benzodiazepine therapy to placebo in terms of safety. The majority of the identified reviews were of poor methodological quality and/or lacked adequate reporting. Nonetheless, emerging from two reviews was a consistent finding from mostly high-quality observational studies of an association between long-term use of benzodiazepines and dementia. There remains little or conflicting evidence pertaining to the other safety outcomes. No studies were identified that addressed the efficacy and safety of long-term versus short-term benzodiazepine use. From the literature search, two studies (i.e., one SR and one RCT) were identified that assessed the efficacy of long-term benzodiazepine use compared to placebo. These two studies did not meet our pre-specific inclusion criteria as this review was interested in comparing the efficacy of long-term versus short-term benzodiazepine use. Briefly, the SR was the aforementioned review on patients with schizophrenia. 12 The study found evidence favoring benzodiazepine in terms of the global outcomes (i.e., relapse reduction and clinician rated improvement) although inconsistencies existed between trials in terms of psychiatric and behavioral outcomes. The other was a double-blind, placebo-controlled crossover RCT 14 on patients with COPD and insomnia who were randomized to either temazepam 10 mg once daily or placebo for one week followed by a one week wash-out prior to switching to the other intervention for a final week. No difference was observed in the respiratory parameters between the treatment groups. Although some sleep outcomes were found to be statistically significantly better with benzodiazepines compared to placebo (i.e., total sleep time; duration of Stage 2 sleep; and sleep latency), these findings must be interpreted with care as multiple treatment comparisons were made which increases the probability of that findings are due to random Long-term Use of Benzodiazepines 6

chance. The efficacy of long-term benzodiazepine compared to short-term benzodiazepine therefore remains uncertain. In conclusion, no studies were identified that addressed the efficacy and safety of long-term benzodiazepine use to short-term use. There is limited evidence on the long-term safety of benzodiazepine compared to placebo or non-users except for a plausible association with dementia. However, it remains unclear how long-term is defined in the existing literature. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Long-term Use of Benzodiazepines 7

REFERENCES 1. Amarasuriya UK, Myles PR, Sanders RD. Long-term benzodiazepine use and mortality: are we doing the right studies? Curr Drug Saf. 2012 Nov 1;7(5):367-71. 2. Gallagher HC. Addressing the issue of chronic, inappropriate benzodiazepine use: how can pharmacists play a role? Pharmacy [Internet]. 2013 Sep 25 [cited 2015 Aug 11];1(2):65-93. Available from: http://www.mdpi.com/2226-4787/1/2/65/htm 3. Donoghue J, Lader M. Usage of benzodiazepines: A review. Int J Psychiatry Clin Pract. 2010 Jun;14(2):78-87. 4. Egan M, Moride Y, Wolfson C, Monette J. Long-term continuous use of benzodiazepines by older adults in Quebec: prevalence, incidence and risk factors. J Am Geriatr Soc. 2000 Jul;48(7):811-6. 5. Smink BE, Egberts AC, Lusthof KJ, Uges DR, de Gier JJ. The relationship between benzodiazepine use and traffic accidents: A systematic literature review. CNS Drugs. 2010 Aug;24(8):639-53. 6. Benzodiazepines in older adults: a review of clinical effectiveness, cost-effectiveness, and guidelines [Internet]. Ottawa: CADTH; 2011 Jan. [cited 2015 Jul 21]. (Rapid response report: peer-reviewed summary with critical appraisal). Available from: https://www.cadth.ca/sites/default/files/pdf/m0022_benzodiazepines_in_the_elderly_l3_e. pdf 7. Summary of product characteristics for benzodiazepines as anxiolytics or hypnotics [Internet]. London (GB): European Medicines Agency; 1994. [cited 2015 Aug 11]. Available from: http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2009/09/wc 500003774.pdf 8. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2015 Jul 7];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1810543/pdf/1471-2288-7-10.pdf 9. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2015 Jul 7];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1756728/pdf/v052p00377.pdf 10. Billioti de Gage S, Pariente A, Begaud B. Is there really a link between benzodiazepine use and the risk of dementia? Expert Opin Drug Saf. 2015 May;14(5):733-47. 11. Zhong G, Wang Y, Zhang Y, Zhao Y. Association between benzodiazepine use and dementia: a meta-analysis. PLoS ONE [Internet]. 2015 May 27 [cited 2015 Jul 9];10(5):e0127836. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4446315 Long-term Use of Benzodiazepines 8

12. Sim F, Sweetman I, Kapur S, Patel MX. Re-examining the role of benzodiazepines in the treatment of schizophrenia: a systematic review. J Psychopharmacol. 2015 Feb;29(2):212-23. 13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009 Oct;62(10):e1-e34. 14. Stege G, Heijdra YF, van den Elshout FJ, van de Ven MJ, de Bruijn PJ, van Sorge AA, et al. Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD. Respir Med [Internet]. 2010 Apr [cited 2015 Jul 8];104(4):518-24. Available from: http://www.sciencedirect.com/science/article/pii/s0954611109003576 Long-term Use of Benzodiazepines 9

APPENDIX 1: Selection of Included Studies 175 citations identified from electronic literature search and screened 169 citations excluded 6 potentially relevant articles retrieved for scrutiny (full text, if available) 1 relevant report retrieved from other sources (grey literature, hand search) 7 potentially relevant reports 3 reports excluded: - comparator not of interest (3) 4 reports included in review Long-term Use of Benzodiazepines 10

APPENDIX 2: Additional References of Potential Interest Previous CADTH Reports Short- and long-term use of benzodiazepines in patients with generalized anxiety disorder: a review of guidelines [Internet]. Ottawa: CADTH; 2014 Jul 28. (Rapid response report: summary with critical appraisal). [cited 2015 Jul 3]. Available from: https://www.cadth.ca/media/pdf/htis/dec- 2014/RC0567%20Limiting%20Benzodiazepines%20Final.pdf Randomized Controlled Trial Comparator not of Interest Nardi AE, Freire RC, Mochcovitch MD, Amrein R, Levitan MN, King AL, et al. A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine. J Clin Psychopharmacol. 2012 Feb;32(1):120-6. Pomara N, Lee SH, Bruno D, Silber T, Greenblatt DJ, Petkova E, et al. Adverse performance effects of acute lorazepam administration in elderly long-term users: pharmacokinetic and clinical predictors. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jan 2;56:129-35. Stege G, Heijdra YF, van den Elshout FJ, van de Ven MJ, de Bruijn PJ, van Sorge AA, et al. Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD. Respir Med [Internet]. 2010 Apr [cited 2015 Jul 8];104(4):518-24. Available from: http://www.sciencedirect.com/science/article/pii/s0954611109003576 Long-term Use of Benzodiazepines 11

APPENDIX 3: Characteristics of Included Systematic Reviews First Author, Publication Year, Country Billioti de Gage, 2015, 10 France Study design, Length of Follow-up SR of observational studies on relationship between BZD use and dementia Patients Characteristics, Sample Size (n) 10 studies, 4 cohort and 6 case-control studies Intervention (dosage strength) BZD (defined as: ever use, current use or former use) Comparator(s) Non-user or never users of BZD Outcomes - Dementia Search dates between January 1992 to September 2014. Summary of study details not provided Sim, 2015, 12 UK Zhong, 2015, 11 China Restricted to English. SR of RCTs on BZD for schizophrenia Included literature up to December 2013. Restricted to English. SR/MA of observational studies on relationship between BZD use and dementia Included literature up to August 2014. 26 studies of which 7 studies compared BZD vs placebo (sample size ranged from 12 to 93), 50% males, mean age ranged 33 to 40 years BZD (n=152) Placebo (n=179) 6 studies, 45 391 patients (sample size ranged from 1063 to 25 140) BZD, in which most commonly studied was diazepam (5 studies) BZD (defined as: ever use, recent use or past use) Placebo Never users - Global measures (e.g. CGI, GAS, relapse) - Psychiatric and behavioural measures (e.g., PANSS, BPRS, TSRS) - Safety - Dementia Amarasuriya, 2012, 1 UK Language restriction unspecified SR of observational studies on relationship between BZD and mortality 12 studies (sample size ranged from 403 to1 099 830) BZD Unclear - Mortality Search date unspecified. Language restriction unspecified BPRS = brief psychiatric rating scale; BZD = benzodiazepine; CGI = clinical global impression; GAS = global assessment; MA = meta-analysis; PANSS = positive and negative syndrome scale; QD = quaque die (once per day); RCT = randomized controlled trial; SR = systematic review; TSRS = target symptom rating scale; UK = United Kingdom Long-term Use of Benzodiazepines 12

APPENDIX 4: Critical Appraisal of Included Systematic Reviews First Author, Publication Year, Country Billioti de Gage, 2015, 10 France Sim, 2015, 12 UK Zhong, 2015, 11 China Strengths Provides list of included studies alongside some baseline characteristics (e.g., population size, age, study duration). Critical appraisal using Newcastle-Ottawa scale. Includes a section disclosing potential conflict of interest. Clear description of literature search, with multiple databases searched and duplicate independent study selection using clearly defined screening criteria. Quality assessment conducted using the CONSORT guidelines. Includes a section disclosing potential conflict of interest. Clear description of literature search, with multiple databases searched and duplicate independent study selection using defined screening criteria. Critical appraisal using Newcastle-Ottawa scale conducted. Provides list of included studies alongside some baseline characteristics (e.g., population size, age, study duration). Includes a section disclosing potential conflict of interest. Limitations Lacks reporting of methodological details such as the screening criteria, whether duplicate independent study selection was performed and how data were extraction. Only searched one database and did not consider grey literature sources. Missing a list of excluded studies. Publication bias not considered. Did not consider grey literature sources. Uncertain of the time range encompassed by the search as the start date is not provided. Omitted providing a list of included & excluded studies alongside the characteristics of the included studies. Critical appraisal not performed. Publication bias not considered. Did not consider grey literature sources. Uncertain of the time range encompassed by the search as the start date is not provided. Missing a list of excluded studies. Publication bias considered although inappropriate given the number of studies identified. Long-term Use of Benzodiazepines 13

First Author, Publication Year, Country Amarasuriya,2012, 1 UK UK = United Kingdom Strengths Provides list of included studies alongside some baseline characteristics (e.g., population size, study duration). Includes a section disclosing potential conflict of interest. Limitations Only searched one database and did not consider grey literature sources. Uncertain of the time range encompassed by the search as the start date is not provided. Lacks reporting of methodological details such as the screening criteria, whether duplicate independent study selection was performed and how data were extraction. Missing a list of excluded studies. Critical appraisal not performed. Publication bias not considered. Long-term Use of Benzodiazepines 14

APPENDIX 5: Summary of Main Study Findings and Author s Conclusions First Author, Publication Year, Country Billioti de Gage, 2015, 10 France Sim, 2015, 12 UK Main Findings of the Systematic Review 10 observational studies comprising 82,204 patients. Safety: o 8 out of 10 studies concluded a statistically increased risk of dementia associated with BZD. The other two studies either did not have sufficient sample size or found a paradoxical protective association [speculated to be due to misclassification of exposure]. o Most studies conducted in elderly who are more vulnerable to neurocognitive side effects. No conclusions can be drawn concerning possible excess risk for younger population. o One trial found no increased risk for cumulative use <3 months. Another similar suggests symptoms regress after discontinuations only when treatment was short and not when it was long. 26 RCTs in which seven specifically compared BZD against placebo, comprising 309 patients with schizophrenia. Only results of relevant comparisons presented: Clinical effectiveness: o Global outcomes (subjective assessment): 2/5 studies reported that BZD was significantly superior to placebo for relapse reduction and global outcomes over the short-term; 3/5 studies reported no difference [although in two of these studies, a trend favoring BZD was present]. o Psychiatric & other behavioural outcomes: - Short-term studies: inconsistent findings; 2/4 short-term studies found BZD significantly superior to placebo, one study found that paranoid symptoms deteriorated in the BZD arm. - Long-term studies: none found. Safety: None reported Authors Conclusions literature points to the existence of a 1.5- to 2-fold increased risk of dementia following the long-term use of BZDs by the elderly. At this stage, the causal nature of this association is far from being established but could be considered at least possible. A major finding is that treatments respecting recommended durations of use would not be concerned. These two points make it crucial to avoid unjustified initiation and uncontrolled chronic use. (p. 744) BZD superiority over placebo was found for global, psychiatric and behavioural outcomes, but inferiority to antipsychotics on longer-term global outcomes. Conflicting evidence exists regarding the addition of BZDs to antipsychotics; thus the use of BZDs in clinical practice and antipsychotic trials should be limited. (p. 212) Long-term Use of Benzodiazepines 15

First Author, Publication Year, Country Zhong, 2015, 11 China Amarasuriya,2012, 1 UK Main Findings of the Systematic Review 6 observational studies comprising 45,391 patients. Safety: Ever users vs. never users Recent users vs. never users Past users vs. never users Pooled adjusted RR for dementia (95% CI) random effects 1.49 (1.30 to 1.72) 1.55 (1.31 to 1.83) 1.55 (1.17 to 2.03) o Risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR, 1.22, 95% CI: 1.18 to 1.25) 12 observational studies comprising >1,143,927 patients. Safety: Findings on mortality were mixed and each had significant methodological flaws limiting definite conclusions and making meta-analysis inappropriate. o Three potential subgroups vulnerable to BZD: renal failure, lung disease, recent hospital admission. Authors Conclusions On the basis of either unadjusted or adjusted risk estimates, our study consistently indicates that long-term BZD use is associated with an increased risk of dementia. Due to limited studies, especially doseresponse analysis, and potential reverse causation, these findings should be treated with caution. (p.13) We identified three potentially at risk groups of patients, those with renal disease, lung disease and those recently hospitalised. However methodological limitations including selection bias, vague descriptors of BZD use and inappropriate grouping together of BZDs with other medications, preclude definitive conclusions. (p. 367) BZD = benzodiazepine; CI = confidence interval; HR = hazard ratio; P = probability value; RCT = randomized controlled trial; RR = risk ratio; SR = systematic review; UK = United Kingdom Long-term Use of Benzodiazepines 16