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New research supports current guidelines cautioning against long-term use of benzodiazepines.
The study of more than 5000 older adults found that benzodiazepine use was associated with an accelerated reduction in the volume of the hippocampus and amygdala — brain regions involved in memory and mood regulation. However, benzodiazepine use overall was not associated with an increased risk for dementia.
The findings suggest that benzodiazepine use "may have subtle, long-term impact on brain health," lead investigators Frank Wolters, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues wrote.
The study was published online on July 1 in BMC Medicine.
Conflicting Evidence
Benzodiazepines are commonly prescribed in older adults for anxiety and sleep disorders. Though the short-term cognitive side effects are well-documented, the long-term impact on neurodegeneration and dementia risk remains unclear. Some studies have linked benzodiazepine use to an increased risk for dementia, whereas others have not.
Wolters and colleagues assessed the effect of benzodiazepine use on long-term dementia risk and on imaging markers of neurodegeneration in 5443 cognitively healthy adults (mean age, 71 years; 57% women) from the population-based Rotterdam Study.
Benzodiazepine use between 1991 and 2008 was determined using pharmacy dispensing records, and dementia incidence was determined from medical records.
Half of the participants had used benzodiazepines at any time in the 15 years before baseline (2005-2008); 47% used anxiolytics, 20% used sedative-hypnotics, 34% used both, and 13% were still using the drugs at the baseline assessment.
During an average follow-up of 11 years, 13% of participants developed dementia.
Overall, use of benzodiazepines was not associated with dementia risk compared with never-use (hazard ratio [HR], 1.06), irrespective of cumulative dose.
The risk for dementia was somewhat higher with any use of anxiolytics than with sedative-hypnotics (HR, 1.17 vs HR, 0.92), although neither was statistically significant. The highest risk estimates were observed for high cumulative dose of anxiolytics (HR, 1.33).
Sensitivity analyses of the two most commonly used anxiolytics found no differences in risk between use of short half-life oxazepam and long half-life diazepam (HR, 1.01 and HR, 1.06, respectively, for ever-use compared with never-use for oxazepam and diazepam).
Brain Atrophy
The researchers investigated potential associations between benzodiazepine use and brain volumes using brain MRI imaging from 4836 participants.
They found that current use of a benzodiazepine at baseline was significantly associated with lower total brain volume as well as lower hippocampus, amygdala, and thalamus volume cross-sectionally and with accelerated volume loss of the hippocampus and, to a lesser extent, amygdala longitudinally.
Imaging findings did not differ by type of benzodiazepine used or cumulative dose.
"Given the availability of effective alternative pharmacological and non-pharmacological treatments for anxiety and sleep problems, it is important to carefully consider the necessity of prolonged benzodiazepine use in light of potential detrimental effects on brain health," the authors wrote.
Risks Go Beyond the Brain
Commenting on the study for Medscape Medical News, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, Florida, noted that "chronic benzodiazepine use may reduce neuroplasticity, potentially interfering with the brain's ability to form new connections and adapt.
"Long-term use can lead to downregulation of GABA receptors, altering the brain's natural inhibitory mechanisms and potentially contributing to tolerance and withdrawal symptoms. Prolonged use can also disrupt the balance of various neurotransmitter systems beyond just GABA, potentially affecting mood, cognition, and overall brain function," said Lakhan, who was not involved in the study.
"While the literature is mixed on chronic benzodiazepine use and dementia risk, prolonged use has consistently been associated with accelerated volume loss in certain brain regions, particularly the hippocampus and amygdala," which are responsible for memory, learning, and emotional regulation, he noted.
"Beyond cognitive impairments and brain volume loss, chronic benzodiazepine use is associated with tolerance and dependence, potential for abuse, interactions with other drugs, and increased fall risk, especially in older adults," Lakhan added.
Current guidelines discourage long-term use of benzodiazepines due to risk for psychologic and physical dependence; falls; and cognitive impairment, especially in older adults. Nevertheless, research shows that 30%-40% of older benzodiazepine users stay on the medication beyond the recommended period of several weeks.
Donovan T. Maust, MD, Department of Psychiatry, University of Michigan Medical School, Ann Arbor, told Medscape Medical News these new findings are consistent with other recently published observational research that suggest benzodiazepine use is not linked to dementia risk.
"I realize that such meta-analyses that find a positive relationship between benzodiazepines and dementia are out there, but they include older, less rigorous studies," said Maust, who was not part of the new study. "In my opinion, the jury is not still out on this topic. However, there are plenty of other reasons to avoid them — and in particular, starting them — in older adults, most notably the increased risk of fall injury as well as increased overdose risk when taken along with opioids."
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