Benzodiazepines – commonly prescribed to treat anxiety and insomnia – have previously been linked to cognitive impairment and dementia when used long term, but until now the mechanisms underpinning this have remained unknown. Now, a study, published recently in Nature Neuroscience, has finally shed some light on how the widely used drugs might be affecting the brain.
When used in the short term, benzodiazepines, such as diazepam (Valium), are considered to be safe and effective. However, sustained use over long periods can lead to physical dependence, and, particularly in older patients, cognitive decline, including dementia.
The new study set out to understand why this might be and found that, in a mouse model, diazepam causes loss of neuronal connections in the brain. Specifically, it impairs dendritic spines – part of the neuron that helps to transmit electrical signals between nerve cells. A more dramatic loss of spines was present in animals given higher doses of diazepam, while the loss was more gradual for those on a lower dose over a longer period of time.
To facilitate this spine loss, diazepam interacted with microglia – immune cells that are the first and main form of defense in the central nervous system. By binding to a protein, called the translocator protein (TSPO), on the surface of microglial organelles, the drug is able to activate the microglia, causing dendritic spine loss and degradation of synapses – the connections between neurons.
“It was known that microglia play an important role in eliminating synapses both during brain development and in neurodegenerative diseases,” Dr Yuan Shi and Mochen Cui, co-authors of the study, said in a statement. “But what really surprised us was that such well-researched drugs as benzodiazepines influence this process.”
The team administered a daily dose of diazepam – enough to induce sleep – to mice for several weeks. The mice suffered synapse loss, which led to cognitive impairment, but was ultimately reversible once treatment stopped.
“Based on these findings, it seems likely that, as a consequence of benzodiazepine use, TSPO-mediated spine loss accelerated cognitive decline and, thus, precipitated clinical dementia,” the authors write in the study.
In light of this, they recommend that clinicians rethink the treatment of anxiety and sleep disorders, particularly in people already at risk of dementia.
“Drugs that are known to have no binding affinity to TSPO should be preferred where possible,” they said.
Although it's important to note that the study was carried out in mice and further research would need to be carried out in humans, the findings could be pertinent to a number of disorders, and could “constitute a novel approach for the treatment of neurodegenerative diseases,” the authors conclude.
But the implications of the research reach far beyond this. The study also notes that benzodiazepines are known to affect the peripheral nervous system: “Thus, the biological mechanism, which we describe here, should also be considered in the context of other neuropsychiatric conditions. For instance, a common [genetic variation] in TSPO has been associated with bipolar disorder.”