16 Sep 2014

Valium can make people pleasantly foggy, which is a reason doctors prescribe it to relieve stress during outpatient surgeries and for anxiety and panic attacks. However, a new study suggests that the effects of prolonged use of benzodiazepines such as Valium, aka benzodiazepine, may extend far beyond that initial blur. As reported September 9 in the British Medical Journal, people highly exposed to benzodiazepines may nearly double their risk of developing Alzheimer’s disease (AD) later on. The study, led by Bernard Bégaud at the University of Bordeaux in France, is the latest and most thorough of several previous reports that came to similar conclusions.

“One study after another starts to build a case,” commented Lon Schneider of the University of Southern California in Los Angeles, who was not involved in the work. “All this together argues that geriatricians should be even more conservative than they already are in prescribing benzodiazepines.”

Benzodiazepines are usually prescribed for short-term relief of anxiety or insomnia. Due to their potentially addictive qualities, they are not seen as a long-term solution. Elderly people are reportedly especially sensitive to the drugs’ cognitive side effects, which include memory loss, yet long-term use is most prevalent in older people (see Egan et al., 2000 and Neutel, 2005).

For more than a decade, studies have suggested that benzodiazepines may raise the risk of dementia (see Lagnaoui et al., 2002, Wu et al., 2009, Gallacher et al., 2012, and Billioti de Gage et al., 2012). However, these findings were plagued by the possibility of reverse causality: Could benzodiazepines correlate with the development of dementia simply because the drugs are prescribed to people already displaying early signs of disease? Disentangling the effects of the drugs from the disorders they are designed to treat is tricky. In an attempt to do this better than previous studies, Bégaud drew from a large cohort and took cumulative benzodiazepine exposure into account.

First author Sophie Billioti de Gage and colleagues took advantage of Quebec’s sizable medical database, which contains clinical and prescription drug information for everyone covered by the province’s public health care plan. The researchers analyzed records from nearly 1,800 people over the age of 66 who had been recently diagnosed with AD, and compared them with records from more than 7,000 age-matched controls. All records in the study went back at least six years prior to the initial dementia diagnosis, and any benzodiazepine use must have been initiated at least five years prior to diagnosis.

In this dataset, benzodiazepine use was associated with a 50 percent increase in AD risk. By looking at how long benzodiazepines were prescribed, the researchers further determined that while brief stints of benzodiazepine use did not noticeably raise AD risk, cumulative exposure of more than three months on these drugs associated with a 32 percent bump in risk of developing AD five to 10 years later. The risk increased 84 percent in people taking the drugs for more than six months. Reports of anxiety, depression, or insomnia themselves did not correlate with AD, and adjustment for these variables only slightly reduced benzodiazepine-associated AD risk.

To further parse the relationship between benzodiazepine exposure and AD, the researchers compared people who took long-acting versus short-acting forms of the drug. Short-acting benzodiazepines are often prescribed for insomnia, whereas their long-acting counterparts (such as Valium) are more commonly prescribed to relieve anxiety. The researchers found that people who took long-acting benzodiazepines were 70 percent more likely to develop AD than controls, whereas people who were prescribed short-acting drugs had a 43 percent boost in risk.

Schneider said that by measuring the relationship between cumulative benzodiazepine exposure and dementia risk, as well as controlling for the confounding variables of anxiety and insomnia, the researchers present the most convincing argument yet that the drugs raise AD risk. However, he added, it would be difficult to prove with complete certainty that the drugs cause neurodegeneration. 

Billioti de Gage agrees. “The nature of the link found in our study—causal or not—is still not definitive, but our conclusions (dose effect relationship) reinforce the suspicion of a possible direct association,” she wrote in an email to Alzforum. “For people needing or using benzodiazepines it seems crucial to encourage physicians to carefully balance the benefits and risks when initiating or renewing a treatment,” she added.

Jenny McCleery of Oxford Health NHS Foundation Trust in Banbury, England, said that the evidence of a causal link would never be absolute, but that the evidence was sufficient to warrant increased caution in prescribing benzodiazepines. She added that clinicians should discuss these risks with patients. “This is something patients should be able to weigh in their decision making. If they continue treatment, it could put them at risk for cognitive decline,” she said.

In an accompanying editorial, Kristine Yaffe of the University of California, San Francisco, and Malaz Boustani of the Indiana University in Indianapolis lauded the study for its rigorous methods and controls, and said the results suggested that exposure to benzodiazepines may be a modifiable AD risk factor. Yaffe and Boustani also proposed more vigilant monitoring systems be put in place to ensure that the aging population is not prescribed unnecessary medications, including benzodiazepines. “Better surveillance for cognitive side effects could improve therapeutic decisions among doctors treating high risk older adults with multiple chronic conditions,” they wrote, “and hopefully, eventually, help to reduce the burden of cognitive impairment worldwide.”

—Jessica Shugart

Comments

1. • Bengt Winblad
     Karolinska Institute
   • Posted: 16 Sep 2014
   • Paper: Benzodiazepine use and risk of Alzheimer's disease: case-control study.

   As the authors state, it still cannot be ruled out that benzodiazepine use might be an early marker of a dementia disorder or a condition associated with an increased risk of dementia. Also, it is important to separate a possible long-term effect of these drugs on the progression of a dementia, from the well-known cognitive side effects of an ongoing benzodiazepine treatment. This study demonstrated a significant association between benzodiazepine use and risk of dementia also in persons for whom benzodiazepine treatment was discontinued for at least one year before the date of diagnosis; a finding which would argue against a direct cognitive side effect of the treatment. However, other drugs with potential negative effects on cognition may be over-represented in bensodiazepine users – both present and former. So, as the analyses were not adjusted for the use of such drugs, we cannot rule out the possibility that current medication may play a role in the observed increased risk of dementia.

   View all comments by Bengt Winblad

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References

Paper Citations

1. 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. PubMed.
2. Neutel CI. The epidemiology of long-term benzodiazepine use. Int Rev Psychiatry. 2005 Jun;17(3):189-97. PubMed.
3. Lagnaoui R, Bégaud B, Moore N, Chaslerie A, Fourrier A, Letenneur L, Dartigues JF, Moride Y. Benzodiazepine use and risk of dementia: a nested case-control study. J Clin Epidemiol. 2002 Mar;55(3):314-8. PubMed.
4. Wu CS, Wang SC, Chang IS, Lin KM. The association between dementia and long-term use of benzodiazepine in the elderly: nested case-control study using claims data. Am J Geriatr Psychiatry. 2009 Jul;17(7):614-20. PubMed.
5. 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). J Epidemiol Community Health. 2012 Oct;66(10):869-73. Epub 2011 Oct 27 PubMed.
6. Billioti de Gage S, Bégaud B, Bazin F, Verdoux H, Dartigues JF, Pérès K, Kurth T, Pariente A. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012 Sep 27;345:e6231. PubMed.

Further Reading

Papers

1. McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in Alzheimer's disease. Cochrane Database Syst Rev. 2014 Mar 21;3:CD009178. PubMed.