Long-term benzodiazepine use linked to shrinkage in two brain regions

Although the overall use of benzodiazepines does not appear to increase the risk of dementia, long-term use is associated with a reduction in the volume of critical brain areas, such as the hippocampus and the amygdala, according to new research published in BMC Medicine. This finding supports current medical guidelines that caution against prolonged benzodiazepine use.

Benzodiazepines are a class of medications commonly prescribed to alleviate anxiety and insomnia. Common benzodiazepines include diazepam (Valium), alprazolam (Xanax), and lorazepam (Ativan). These drugs function by enhancing the effect of a neurotransmitter called gamma-aminobutyric acid (GABA), which promotes relaxation and reduces brain activity.

Due to their calming effects, benzodiazepines are among the most frequently prescribed psychotropic medications in developed countries. However, concerns have been raised about their long-term use, especially among older adults, due to risks of dependence, falls, and potential cognitive decline.

The impetus for this study stemmed from conflicting evidence about the long-term effects of benzodiazepines on cognitive health. While some animal studies suggested that benzodiazepines might protect the brain by reducing inflammation, others indicated they could harm the brain by promoting the buildup of harmful proteins associated with dementia.

Previous human studies also yielded mixed results, with some suggesting an increased dementia risk and others finding no such link. This study aimed to clarify these effects by investigating both the risk of dementia and changes in brain structure over time.

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“Our interest in this topic was raised by the observation that benzodiazepines are the most commonly prescribed medications in developed countries, and 30-40% of older adults continues use beyond the recommended period of several weeks, while several recent studies indicated that benzodiazepines might have long-term adverse effects on cognition,” said study author Ilse vom Hofe of the Erasmus University Medical Center.

The researchers conducted their study using data from the Rotterdam Study, a large, ongoing research project initiated in 1990 to explore common diseases among older adults. The study included 5,443 participants aged 60 and above who were free from cognitive impairment at the start. These participants underwent follow-up assessments every four years, which included cognitive tests and brain imaging scans. Information on benzodiazepine use was obtained from pharmacy records, allowing researchers to track the duration and dosage of medication use.

To assess the impact of benzodiazepines on dementia risk, the researchers used statistical models to compare the incidence of dementia among benzodiazepine users and non-users. They accounted for various factors that could influence dementia risk, such as age, sex, education, and health conditions like diabetes and heart disease.

In addition to dementia assessments, the study also focused on brain imaging data from 4,836 participants who had undergone at least one MRI scan. These scans measured the volumes of different brain regions, including the hippocampus and amygdala, which are crucial for memory and emotion.

The study’s findings revealed no significant association between benzodiazepine use and an increased risk of developing dementia. This result contrasts with some earlier studies that suggested a higher risk.

But the researchers observed that benzodiazepine use was linked to a subtle reduction in the volume of the hippocampus and, to a lesser extent, the amygdala over time. These brain regions are known to shrink as part of the aging process, and accelerated shrinkage can be a marker of neurodegeneration.

“People should take away from our study that benzodiazepine use was not associated with increased dementia risk,” vom Hofe told PsyPost. “However, benzodiazepine use was associated with sub-clinical accelerated reduction in hippocampal and to a lesser extent amygdalar volume over time, underlining current guidelines cautioning against prolonged benzodiazepine use.”

One of the strengths of this study is its robust design and long follow-up period, which allowed for a thorough investigation of both dementia risk and brain changes. The researchers also took into account a wide range of factors that could confound the results, such as the presence of anxiety and sleep disorders, which are both common reasons for benzodiazepine prescriptions and potential risk factors for dementia.

However, the study has some limitations. While the exclusion of participants with cognitive impairment at baseline helped reduce the risk of reverse causation—where cognitive decline leads to benzodiazepine use rather than the other way around—it may also have led to an underestimation of the drug’s adverse effects. Additionally, the study population was predominantly white, which may limit the generalizability of the findings to other ethnic groups.

“Our results are based on a cognitively healthy population, possible adverse effects of benzodiazepine use in people with cognitive impairment warrant further investigation,” vom Hofe noted.

Despite these limitations, the study’s findings have important implications for the use of benzodiazepines, particularly among older adults. The observed reduction in hippocampal volume associated with benzodiazepine use, even in the absence of increased dementia risk, underscores the importance of caution when prescribing these medications for extended periods. The hippocampus plays a crucial role in memory formation, and its shrinkage is often seen in neurodegenerative diseases like Alzheimer’s.

The study also suggests several directions for future research. Further investigations could explore whether different types of benzodiazepines have varying impacts on brain health. For instance, this study found that high cumulative doses of anxiolytics, which are benzodiazepines prescribed for anxiety, were associated with a higher risk of dementia compared to sedative-hypnotics, which are prescribed for sleep disorders. Understanding these differences could help guide safer prescribing practices.

“This research is part of a line of research investigating the effects of commonly used medications on dementia risk, with the ultimate goal to prevent or delay the onset of dementia,” vom Hofe said.

The study, “Benzodiazepine use in relation to long-term dementia risk and imaging markers of neurodegeneration: a population-based study,” was authored by Ilse vom Hofe, Bruno H. Stricker, Meike W. Vernooij, M. Kamran Ikram, M. Arfan Ikram, and Frank J. Wolters.