Benzodiazepine use and risk of Alzheimer’s disease: case-control study
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5205 (Published 09 September 2014) Cite this as: BMJ 2014;349:g5205
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Benzodiazepine prescriptions, use, abuse, and self medication in Greece remain extremely high.
Even 6% of educated medical students ingest benzodiazepines illegally!
In Greek prisons, chronic benzodiazepine use with poor monitoring is even more prevalent than in the general population!
References
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306042/
http://www.icspres.org/uploads/4/7/5/3/4753640/suffering_at_the_hands_of...
Competing interests: No competing interests
In my opinion people with early Alzheimer's disease using benzodiazepines for anxiety, agitation and insomnia. For this reason, benzodiazepines are not implicated in Alzheimer's disease, but patients with symptoms of early dementia using these medications. The statistical data are, for this reason, not very reliable.
Competing interests: No competing interests
I commend the authors on this well-designed and rigorously conducted study (1). The finding that use of benzodiazepines is associated with an increased risk for dementia is consistent their previous prospective study (2) and with the findings from the Caerphilly Prospective Study (3).
Their conclusion is logical and they provide a plausible biological explanation which invokes a possible decrease in cognitive reserve capacity consequent to benzodiazepine-mediated down-regulation of GABA receptors.
The concern of reverse causation deserves scrutiny because there may be a biologically plausible explanation for that as well. Are there processes that occur in these patients during the years prior to diagnosis which involve GABAergic systems?
There is evidence that GABAA messenger RNA expression in post-mortem hippocampus of human mild cognitive impairment (MCI) subjects (4), and that GABAA binding potential measured by carbon-11 flumazenil binding is decreased in patients with early Alzheimer’s disease in brain regions which show the greatest degree of neuronal loss in post-mortem studies (5). Posterior cingulate GABA and glutamate/glutamine were found to be reduced in MCI patients (6).
It is plausible that in the two decades prior to even MCI diagnosis that apolipoprotein E genotype and/or soluble amyloid beta may slowly disrupt the balance of excitatory and inhibitory neurotransmission. This may lead to symptoms which prompt prescribing of benzodiazepines, and may even be part of the neuro-pathologic cascade in AD.
1. Billoti de Gage S, Moride P, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s Disease: case-control study. BMJ 2014;349:g5555
2. Billoti de Gage S, Begaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012;345:e6231
3. Gallacher J, Elwood P, Pickering J, et al. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Community Health 2012;66:869-873
4. Rissman R, Bennett D, Armstrong D. Subregional analysis of GABAA receptor subunit mRNAs in the hippocampus of older persons with and without cognitive impairment. J Chem Neuroanatomy 2004; 28:17-25
5. Pasqual B, Prieto E, Arbizu J, et al. Decreased carbon- 11- flumazenil binding in early Alzheimer’s disease. Brain 2012;135:2817-2825
6. Riese F, Gietl A, Zolch N, et al: Posterior cingulate gamma-aminobutyric acid and glutamate/glutamine are reduced in mild cognitive impairment and are unrelated to amyloid deposition and apolipoprotein E genotype. J Neurobiol Aging 2014;1-7
Competing interests: No competing interests
While a general recommendation is to limit the use of benzodiazepines as a short period of time as feasible for fear of their potentially problematic adverse effects, the reality is that not a few people use them for an extended period of time (1). This is also clearly shown in this important paper in that a majority of those who ever used benzodiazepine were classified as long term users of 180 or more prescribed daily doses (i.e., 590 of 894 cases and 1565 of 2873 controls) (2). As such it would be interesting to focus on the people who continued benzodiazepines throughout versus those who ceased to take them in the middle of the follow up period. This said there would be four groups of people to study: those who continued benzodiazepines throughout and developed Alzheimer’s disease, those who continued benzodiazepines throughout and did not developed Alzheimer’s, those who stopped benzodiazepines midway and developed Alzheimer’s, and those who stopped benzodiazepines midway and did not develop the disease. In so doing a causality (and not a mere association) may be examined more in depth. This would admittedly be still difficult since benzodiazepines may be used on a pro re nata basis (and not continuously) (3) and setting a universally acceptable drug free period for arguing against causing the event in question should be equivocal to date.
References
1. Baldwin DS, Aitchison K, Bateson A, Curran HV, Davies S, Leonard B, Nutt DJ, Stephens DN, Wilson S. Benzodiazepines: risks and benefits. A reconsideration. J Psychopharmacol. 2013 Nov;27(11):967-71. doi: 10.1177/0269881113503509.
2. Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ. 2014 Sep 9;349:g5205. doi: 10.1136/bmj.g5205.
3. Yoshida K, Suzuki T, Uchida H, Mimura M. Absence of evidence that the pro re nata regimen confers benefit: a review of the studies. Int Clin Psychopharmacol. 2013 Sep;28(5):228-37. doi: 10.1097/YIC.0b013e328362db99.
Competing interests: No competing interests
To the editors:
The authors are to be commended on a systematic methodological design in their case control study(1), which has stimulated much debate. There are a few comments to be made regarding the intricate relationship between Alzheimer’s disease and benzodiazepine use.
Firstly, does prodromal symptoms always-equal prescription of benzodiazepines? There is no clear evidence that this is in fact true. While discussion surrounding concern for protopathic bias are valid, I fail to see any strong evidence in the literature that supports this notion. Readers should be aware that protopathic bias in this case is hard to prove given the multiple treatment modalities available for the potential treatment of prodromal symptoms.
Secondly, the concern regarding reverse causation has been and always will be problematic in the complex relationship between Alzheimer’s and benzodiazepines. While readers remark about this frequently, shouldn't we be looking to solutions that could create the ‘ideal’ study. Preferably a study that has a longer follow up (30 years) is warranted. This however is outweighed by the risks and difficulties encountered by such long follow ups. It is feasible to run a 30-year study? There answer is it is possibly not. The costs as well as the ability to follow up individuals for that long are demanding. I encourage readers to think about where do we draw the line? Will further observation studies provide additional answers? I believe our answers to this complex interaction will not come from observational studies with the current state of research nor would it be feasible or ethical to run a randomised control trial. The answers will start to appear when we are able to identify the prodromal phase of Alzheimer’s (a massive challenge in itself). Great progress has already been made through development of biomarkers(2-4) and advancement in neuropsychology(4). If we are able to detect this stage accurately and precisely, we would hopefully be able to limit any concern regarding reverse causation.
It is important that we appreciate the clinical implications and relevance of the above study to our elderly population. There is growing evidence on the long-term cognitive effects of benzodiazepines(5-8) and although concerns around protopathic basis are valid, we should be aware our own limitations and look to future advancement of science and technology to help provide us with a clearer picture of this complex link.
References
1. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. Bmj. 2014;349:g5205.
2. Molinuevo JL, Sanchez-Valle R, Llado A, Fortea J, Bartres-Faz D, Rami L. Identifying earlier Alzheimer's disease: insights from the preclinical and prodromal phases. Neuro-degenerative diseases. 2012;10(1-4):158-160.
3. Lim YY, Maruff P, Pietrzak RH, et al. Abeta and cognitive change: Examining the preclinical and prodromal stages of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2014.
4. Lista S, Garaci FG, Ewers M, et al. CSF Abeta1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2014;10(3):381-392.
5. Lagnaoui R, Begaud B, Moore N, et al. Benzodiazepine use and risk of dementia: a nested case-control study. Journal of clinical epidemiology. 2002;55(3):314-318.
6. Verdoux H, Lagnaoui R, Begaud B. Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychological medicine. 2005;35(3):307-315.
7. Billioti de Gage S, Begaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. Bmj. 2012;345:e6231.
8. Gallacher J, Elwood P, Pickering J, Bayer A, Fish M, Ben-Shlomo Y. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). Journal of epidemiology and community health. 2012;66(10):869-873.
Competing interests: No competing interests
We acknowledge Dr. Kavirajan for his interest in our work and for addressing interesting methodological issues, some of which require additional information.
- First of all, it is important not to confuse statistical and causal associations. Despite our results confirming the association previously found between long-term benzodiazepine (BZD) use and an increased risk of Alzheimer’s disease (AD), we never stated that this association was direct or causal. On the contrary, we devoted a significant part of the Discussion to reviewing various alternative hypotheses including a residual protopathic bias. We even mentioned that BZDs could simply be early markers of a risk factor for AD such as depression, anxiety or insomnia. Having said that, there was no reason not to consider a possible contribution of BZDs to this excess risk of AD, at least owing to the tremendous public health impact such an option would have.
- Concerning the figure of 30% given by Dr. Karavijan for the proportion of BZD users presenting with anxiety, depression or insomnia, there may have been a misinterpretation of our Table 2 comparing the characteristics of cases and controls (and not of BZD users and non-users). Indeed, for cases the proportion of anxiety recorded as a diagnosis in the database was 21.4%. As the proportion of BZD users was less than 50% in the group of cases, it is obvious that the percentage of anxiety in those using BZDs was much higher than 21.4%. The same could be said for depression and insomnia. Moreover, given the therapeutic effects of BZDs on anxiety and insomnia, a lower incidence of these symptoms was expected in prevalent users. As to the comparison with the data of Pelissolo and colleagues,1 it does not seem to be relevant. Indeed, that study (i) was conducted in another country (France), and (ii) included persons aged 18 and over (versus 66 and over in our study), those having used BZDs for at least 6 months i.e. exceeding the duration recommended (real-life use was considered in our study), those having given their written informed consent, etc.
- No clear-cut hypothesis or conclusion can be put forward concerning a putative confounding by alcohol consumption. Confounding would only ensue from an association of alcohol with both BZD use and the risk of AD. The latter is far from being established. Indeed, according to the literature, for regular and « moderate » drinkers, the association wavers between « no effect » and « protective ». Therefore, not considering this variable for adjustment tends rather to be conservative.
- The most challenging comment concerns the as yet unresolved issue of the type of association, if any, between depression, anxiety or insomnia and AD. This point was discussed in our article. First, it seems important not to confuse the protopathic bias, i.e. BZDs having been, at least in part, prescribed to treat pre-diagnosis symptoms of AD, and the possible role of these symptoms as risk factors for this disease. To minimize this bias, it seems sensible to censor prescriptions initiated a few years before the diagnosis of AD. A censored time-window of 5 or 6 years, as in our study, seems to be a realistic compromise. Studying the possible role of depression, anxiety or insomnia identified 10, 20 years before or even more on the risk of AD is another challenge that is probably not feasible at present. To our knowledge, no database or cohort study offers a 30-year follow-up with a sample size large enough to allow subgroup analyses as well as reliable data on (i) drug exposure, (ii) comorbidities and risk factors, and (iii) cognitive disorders. Failing this, the study of interactions and the adjustment on these variables, although not perfect, seems to be the way to go. Whatever the process involved, a conclusion remains: long-term BZD use is associated with an increased risk of AD and the precautionary principle would require considering the worst-case scenario, especially when a suspected risk factor is mostly alterable.
1. Pelissolo A, Maniere F, Boutges B, Allouche M, Richard-Berthe C, Corruble E. [Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice]. L'Encephale 2007;33(1):32-8.
Competing interests: No competing interests
To the editors:
We applaud the work of Billioti de Gage and colleagues who linked benzodiazepine use in older adults to the subsequent development of dementia.1 However, we disagree with their assertions that “Benzodiazepines are indisputably valuable tools for managing anxiety disorders and transient insomnia” and their suggestion that short duration benzodiazepine exposure is consistent with good practice guidelines. A mass of evidence suggests that the benefits of benzodiazepines in older adults rarely, if ever outweigh their risks.
Benzodiazepine risks, whether short-term or chronic, include cognitive impairment,23, delirium,4 respiratory insufficiency,5 falls,6 fall-related injuries such as hip fractures,7 motor vehicle crashes,8 and death.9 Most patients are not warned of these risks before starting these medications.10 The main risk factor for chronic benzodiazepine use is any previous use, so an intended short-duration prescription of these habit-forming medication is likely to lead to their long-term use.11 Chronic benzodiazepine users are rarely prompted to discontinue, despite good evidence for the safety and tolerability of tapering protocols.12
Benzodiazepines’ benefits for anxiety disorders are questionable, especially as they are commonly used in clinical practice. First, the dose of benzodiazepines necessary to provide a clinical response is far higher than that needed to cause harms in older adults – for example, 6-10mg daily of alprazolam is needed to bring about remission from panic disorder,13, and 30-60mg daily of oxazepam was needed for response in (to our knowledge) the only controlled study of benzodiazepines for anxiety disorder in older adults.14. Second, there is growing evidence in anxiety disorders that benzodiazepine use reduces the efficacy of exposure-based cognitive behavior therapy, probably by interfering with learning and memory and preventing habituation to the anxiety.15 Hence, benzodiazepine use may actually perpetuate (rather than treat) many anxiety disorders by preventing naturalistic recovery from them.16
The evidence for benefits of benzodiazepines in insomnia is equally poor. In a meta-analysis, benzodiazepine use resulted in a mean nightly improvement of 25.2 minutes sleep. The number needed to treat for improvement of insomnia was 13, while the number needed to harm was 6.17
Safer treatments for anxiety disorders and insomnia exist and are effective in older adults, including serotonin reuptake inhibitors (for anxiety) and psychotherapy such as relaxation training or cognitive behavioral therapy (for anxiety and/or insomnia).18. These treatments can also be used effectively in combination for chronic anxiety19 . For occasional insomnia or transient anxiety, watchful waiting or other low-intensity intervention are superior to initiating a dangerous and habit-forming medication.
To conclude, Billioti De Gage and colleagues provide more evidence still that deleterious consequences of benzodiazepines in older adults are a large and growing public health problem, given their high rates of use in this age group.20 It is time for their use to be limited, for example to palliative and hospice care or specific treatment-refractory cases, and as a start we recommend the following:
1. Clinicians prescribing these medications to older adults should warn them that their use is not considered best practice.
2. These medications should come with a warning (like that found on cigarette packages) such as “If you are older than 60, use of this medication will increase your risk of cognitive impairment, falls, hip fractures, and death.”
3. Educate health care providers regarding (a) risks of short-term and long-term benzodiazepine use and (b) safe alternatives for the management of anxiety and insomnia.
Doing so would improve the quality of life, safety, and cognitive health, of the large and growing population of older adults.
Competing interests: none to report
Literature cited:
1. Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205.
2. Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry 2005;66 Suppl 2:9-13.
3. 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. Progress in neuro-psychopharmacology & biological psychiatry 2014;56C:129-35.
4. Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing 2011;40(1):23-9.
5. Vozoris NT, Fischer HD, Wang X, Anderson GM, Bell CM, Gershon AS, et al. Benzodiazepine use among older adults with chronic obstructive pulmonary disease: a population-based cohort study. Drugs & Aging 2013;30(3):183-92.
6. Woolcott JC, Richardson KJ, Wiens MO, Patel B, Marin J, Khan KM, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 2009;169(21):1952-60.
7. Finkle WD, Der JS, Greenland S, Adams JL, Ridgeway G, Blaschke T, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc 2011;59(10):1883-90.
8. Meuleners LB, Duke J, Lee AH, Palamara P, Hildebrand J, Ng JQ. Psychoactive medications and crash involvement requiring hospitalization for older drivers: a population-based study. J Am Geriatr Soc 2011;59(9):1575-80.
9. Weich S, Pearce HL, Croft P, Singh S, Crome I, Bashford J, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ 2014;348:g1996.
10. Iliffe S, Curran HV, Collins R, Yuen Kee SC, Fletcher S, Woods B. Attitudes to long-term use of benzodiazepine hypnotics by older people in general practice: findings from interviews with service users and providers. Aging Ment Health 2004;8(3):242-8.
11. Neutel CI. The epidemiology of long-term benzodiazepine use. International review of psychiatry 2005;17(3):189-97.
12. Paquin AM, Zimmerman K, Rudolph JL. Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf 2014;13(7):919-34.
13. Ballenger JC, Burrows GD, DuPont RL, Jr., Lesser IM, Noyes R, Jr., Pecknold JC, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 1988;45(5):413-22.
14. Koepke HH, Gold RL, Linden ME, Lion JR, Rickels K. Multicenter controlled study of oxazepam in anxious elderly outpatients. Psychosomatics 1982;23(6):641-5.
15. Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, et al. A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. The American journal of psychiatry 2014;171(6):640-8.
16. Birk L. Pharmacotherapy for performance anxiety disorders: occasionally useful but typically contraindicated. J Clin Psychol 2004;60(8):867-79.
17. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005;331(7526):1169.
18. Sivertsen B, Omvik S, Pallesen S, Bjorvatn B, Havik OE, Kvale G, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8.
19. Wetherell JL, Petkus AJ, White KS, Nguyen H, Kornblith S, Andreescu C, et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am J Psychiatry 2013;170(7):782-9.
20. Jackson G, Gerard C, Minko N, Parsotam N. Variation in benzodiazepine and antipsychotic use in people aged 65 years and over in New Zealand. N Z Med J 2014;127(1396):67-78.
Competing interests: No competing interests
We are grateful to Dr. Bugden for his interest in our article. As detailed in the Discussion section of the paper, we share most of his remarks. However, we would like to add three comments:
(i) In the article concerned, we paid great attention to avoiding systematically any statement about a direct causal pathway between benzodiazepine (BZD) exposure and the increased risk of dementia observed in long-term users. Several possible explanations were provided in the Discussion, including incomplete controlling for reverse causation. However, we consider our protocol as the most advanced way of minimizing such a bias in the framework of an observational study. Moreover, the risk was found to be increased only for long-term exposure and the results were unchanged when adjusting on possible prodromes of dementia (anxiety, sleep disorders and depression) and when pushing back the index date by one year.
(ii) We obviously agree that Alzheimer’s disease (AD) ensues from a slow process of deterioration starting long before its diagnosis. However, there is little evidence even in the most recent literature that the frequency of symptoms corresponding to indications for BZDs, i.e. insomnia and anxiety, is significantly increased when going back more than 5-6 years before the diagnosis. Moreover, in a previous study based upon a 20-year follow-up,1 the excess risk of dementia was observed only for treatments with BZDs already initiated for at least 5 to 7 years. This finding is congruent with those of the present study. Even though the duration of follow-up was shorter, it was sufficient to capture this excess risk.
(iii) It is essential not to confuse the acute or short-term effects of BZDs on cognition, which are well established and reversible after stopping the treatment, with the putative delayed effects of long-term BZD exposure on the risk of Alzheimer’s disease, which is a priori not reversible and was the scope of our study. Wu and colleagues2 confirmed this duality when showing the reversibility of cognitive impairment in patients treated with BZDs for less than one year but not with longer exposure. As mentioned in the Discussion, for long-term exposure, the odds ratios were 1.72 for treatments still underway at the date of diagnosis and 2.51 for those discontinued for at least one year before. These results plead against pollution by the short-term reversible effects of BZDs. The main public health message is precisely this: beyond the quasi-pharmacological effects of BZDs on cognition, the medical community should be concerned about their possible deleterious effect on the risk of AD. This effect, if any, would ensue only from treatments lasting more than 3 months, i.e. outside the international recommendations (one of the main findings of our study), and the number of cases in excess would be high enough to call for immediate and efficient preventive action to be taken.
References
1. Billioti de Gage S, Begaud B, Bazin F, Verdoux H, Dartigues JF, Peres K, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012;345:e6231.
2. Wu CS, Ting TT, Wang SC, Chang IS, Lin KM. Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry 2011;19(2):151-9.
Competing interests: No competing interests
In their paper “Benzodiazepine use and risk of Alzheimer’s disease: case-control study,”1 Billioti et al report on the results of a logistic regression analysis on a sample of patient data from an administrative database and argue for a “direct association” between benzodiazepine use and development of Alzheimer’s disease (AD). However, their findings and conclusions must be interpreted with caution due to significant methodological and conceptual limitations:
1. The accuracy of the dataset in capturing key clinical data is suspect. How is it possible that less than 30% of benzodiazepine users had diagnoses of anxiety, depression or insomnia? If this is accurate, what are the indications for benzodiazepines in the majority of these subjects? A French study using clinical assessment rather than administrative database records found that the majority of older adults treated with benzodiazepines have diagnosable anxiety and/or depression.2 If, as is likely the case, the primary indication for benzodiazepine use in this patient sample is actually depression and/or anxiety and/or insomnia, the high rates of these diagnoses in the benzodiazepine user group would greatly confound the purported association between benzodiazepine use and AD since these symptoms may be prodromal manifestations of, or risk factors for, AD. The authors’ attempt to control for these factors by entering them as covariates cannot be considered adequate when the values of these variables are so dubious. Even with more accurate data on these diagnoses, the high inter-correlation of benzodiazepine use and diagnoses of depression, anxiety and insomnia would likely preclude an accurate estimate of regression coefficients for these covariates and the key predictive variable of benzodiazepine exposure.
On this critical problem, the authors argue that since rates of diagnoses of insomnia, depression and anxiety are similar in both groups and comparable with prevalence rates in the published literature, then any problem with under-reported diagnoses is unimportant. However, this argument fails to consider that the benzodiazepine user group represents an enriched sample of sorts—one that should have vastly elevated rates of depression, anxiety and insomnia when compared to the rest of the population as demonstrated by Pelissolo et al2. Thus, the lack of a disparity between benzodiazepine users and non-users (and the general population) on rates of these disorders reflects a fundamental problem with the data and hence this analysis.
2. In addition, another potential confounder is alcohol abuse/dependence. The authors note that recent studies have found higher rates of alcohol misuse in than older adults using benzodiazepines versus those not taking such medications, but they incorrectly assert that failure to control for this variable would result in an overly “conservative” estimate of benzodiazepine risk on dementia diagnosis. If the benzodiazepine users included a disproportionate number of alcohol abusers, one would expect to see higher, not lower rates of dementia and cognitive impairment in that group, and hence an overestimate of benzodiazepine effect on dementia risk.3
3. The attempt to control for reverse causality by censoring benzodiazepine exposures less than 5-6 years before dementia diagnosis is inadequate. Available evidence suggests that depression, which frequently involves anxiety and insomnia, may be both a risk factor for AD and other dementias, and a prodromal symptom of these conditions.4 When depression is a risk factor for AD, the time lag between the occurrence of depression and diagnosis of AD is at least 10 years,5 and possibly on the order of 20 or more years. 3 The finding of a larger OR in subjects off benzodiazepines more than 1 year before diagnosis versus in those still on benzodiazepines at diagnosis is consistent with the risk factor mechanism linking depression and AD.
4. Finally, in their discussion, the authors note the reported association between decreased benzodiazepine receptors and AD, implying a “direct” causal effect of benzodiazepine on AD pathology. None of the prevailing models of AD posits a central role for benzodiazepine receptors in the disease pathogenesis, and it is likely that the reduced benzodiazepine receptor expression is simply the result of neuronal cell death that results in decreased expression of serotonin, opioid, glutamate6 and cholinergic receptors,7 and likely multiple other neurotransmitter receptors.
1. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205.
2. Pelissolo A, Maniere F, Boutges B, Allouche M, Richard-Berthe C, Corruble E. [Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice]. Encephale 2007;33:32-8.
3. Zilkens RR, Bruce DG, Duke J, Spilsbury K, Semmens JB. Severe psychiatric disorders in mid-life and risk of dementia in late- life (age 65-84 years): a population based case-control study. Curr Alzheimer Res 2014;11:681-93.
4. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006;63:530-8.
5. Speck CE, Kukull WA, Brenner DE, et al. History of depression as a risk factor for Alzheimer's disease. Epidemiology 1995;6:366-9.
6. Jansen KL, Faull RL, Dragunow M, Synek BL. Alzheimer's disease: changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors--an autoradiographic study. Neuroscience 1990;39:613-27.
7. Court J, Martin-Ruiz C, Piggott M, Spurden D, Griffiths M, Perry E. Nicotinic receptor abnormalities in Alzheimer's disease. Biol Psychiatry 2001;49:175-84.
Competing interests: No competing interests
Re: Benzodiazepine use and risk of Alzheimer’s disease: case-control study
The British Medical Journal; g5205 "Benzodiazepine use and the risk of Alzheimer's disease: case - control study" is an example of purgorative reporting regarding benzodiazepines. Benzodiazepines have been around since the 1960s and are a safe and effective treatment for anxiety disorders according to the "APA Task Force Report on Benzodiazepines" 1991. I am not aware of any studies repudiating this report.
Benzodiazepines have two main side effects - sedation and memory loss. Both are dose related and go away when dose is lowered. They are abused by 1-2% of the population who are also abusing alcohol and street drugs at the same time. Although the researchers themselves stated in their article that the "dose-effect relation between benzodiazepine use and increased rise of Alzheimer's disease might not be causal. The nature of the link cannot be definitely established because the nature of the link...might also be an early marker of a condition associated with an increased risk of dementia." These statements were under "Discussion" and "What this Study Adds" toward the end of the article. Many physicians and the media only read the headlines and draw false conclusions from them. I have had several worried patients ask about this. The researchers missed the mark by not adding that anxiety is often associated with any progressive Organic Brain Syndrome in its early stages.
In my 39 years of private practice psychiatry, I have treated thousands of patients with benzodiazepines. General Anxiety Disorder usually starts in childhood and Panic Disorder usually starts in the mid to late 20s. Patients with anxiety starting in their 50s to 60s without a concomitant physical, psychological or environmental stressor are very often due to a developing Organic Brain Syndrome which includes Alzheimer's. This anxiety is easily treated with benzos. The dose should be lowered as the OBS progresses because confusion and memory loss from a deteriorating brain from the OBS can be exaggerated by the benzo. While research in all areas of psychopharmacology is appropriate, clinical correlation should play a role in coming to speculative conclusions that might be false. When the underlying disease finally shows up claiming the medication may have caused it is overlooking the prodrome of that disease.
Stating this correlation as causative in that article exploits the negatively biased view of the benzos n the medical literature and lay news. This perpetuates the myth of benzodiazepines being dangerous. The media pounces on the headlines further exaggerating them. This frightens the public from taking them and frightens physicians from prescribing them.
Competing interests: No competing interests