Research

The Possibility of Developing Dementia from Long-Term Benzodiazepine Use

Kaitlyn Ramesh


Abstract

Due to their fast-acting and evident effects, benzodiazepines (BZDs, BDZs, BZs) are widely prescribed and taken for treating conditions like anxiety and insomnia. That being said, benzodiazepines are also known for their high risk of dependence, which can lead to cognitive impairment, affecting one’s memory and personality, as well as motor impairment, inducing falls and injuries [1]. Considering these known effects of benzodiazepines, it seems likely that conditions such as dementia may arise from heavy use. This article, however, will discuss how the effects of long-term benzodiazepine use do not correlate with an increase in one’s risk of developing dementia due to interference from multiple confounding factors. 

 

Benzodiazepines

Benzodiazepines refer to a class of psychoactive drugs prescribed for those suffering from anxiety and insomnia. Within benzodiazepines, there are different types varying based on their elimination half-life, or time spent in the bloodstream until its original concentration is halved, and relative potency, which determines the dose prescribed [4]. It is likely for one to have heard about benzodiazepines by their more commonly known brand names. For example, Xanax and Valium are the names that benzodiazepines alprazolam and diazepam are sold under, respectively [2]. Despite there being variation within the benzodiazepines, many share side effects including drowsiness, fatigue, and lethargy [4]. Overdosing on benzodiazepines intensifies these effects to dangerous levels, leading to cognition and motor impairment, as well as increases the risk of dependence. 

The Pharmacology Behind Benzodiazepines

To produce its sedative and hypnotic effects, benzodiazepines operate through the GABAA receptor as a positive allosteric modulator. Out of the three major types of GABA receptors, GABAA is the chlorine-selective ion channel; like the rest of the GABA receptors, the inhibitory neurotransmitter GABA primarily binds to it. Once bound, GABA hyperpolarizes the neuron by inciting a conformational change in its receptor that causes an influx of negatively charged chlorine ions to enter the neuron. This will prevent excitation of the neuron and, on a wider scale, will produce a calming effect on the brain [4]. Benzodiazepines, as positive allosteric modulators, bind to its own receptors on GABAA receptors, which enhances the ability of the GABAA receptor [5]. While calming the brain is a benefit for those who struggle with conditions like insomnia, uncontrolled and increased suppression of brain activity will have more deleterious results.

 

The Pros and Cons to Benzodiazepines

One study shows that 30.6 million adults in the U.S. use benzodiazepines, with 25.3 million prescribed with the drug and 5.3 million misusing it [6]. The prevalence of benzodiazepines is likely due to their multiple uses as anxiolytics, hypnotics, anticonvulsants, and even muscle relaxants. Furthermore, benzodiazepines are fast-acting without any unfavorable, initial side-effects. Serotonergic antidepressants like SSRIs, which can be taken in place of benzodiazepines, often cause nausea and dizziness at the start of treatment and take time to result in any noticeable change [1]. Therefore, having immediate relief for a wide variety of conditions makes taking benzodiazepines seem much more preferable.

However, the negative effects of benzodiazepines can outweigh such benefits. As mentioned earlier, at high doses benzodiazepines lead to impairment in cognition and motor abilities. Additionally, benzodiazepines are associated with dependence since withdrawal symptoms can occur from usage lasting 3 to 4 weeks [7]. Dependence can then lead to BZD-induced toxicity, which in addition to previous side-effects, will result in delirium, anterograde amnesia, and making one prone to injury and falls. Moreover, disinhibition stemming from benzodiazepine use can compromise driving performance. It should be noted that the prescription quantity of benzodiazepines has increased 50% from 2005 to 2015, putting the public at a higher risk of these consequences [8]. In particular, the elderly community is targeted due to the decline in renal function with age, which would lead to a toxic buildup of benzodiazepines in fatty tissue [4]. Unawareness of the downsides to benzodiazepines can lead to misguided prescriptions that endanger a patient’s cognitive ability and life overall. 

 

Benzodiazepine-Induced Dementia Vs. Memory Loss

One recognized concern surrounding long-term benzodiazepine use is potential memory loss. Anterograde amnesia has been detected as a side-effect, which is evident considering that GABAA receptors decrease synaptic plasticity and brain activity. This would then contribute to a decline in retaining memory. Benzodiazepines undermining memory has also been recorded in mice, where the long-term administration of diazepam caused a decrease in their production of BDNF, a neurotrophic factor that enhances memory processing. Similarly, another test on mice under midazolam shows an increase in the phosphorylation of the tau protein; such a result is a precursor to Alzheimer’s disease [10]. These effects from benzodiazepines suggest that dementia could develop from a more long-term use.

Dementia is a set of symptoms that can arise with brain damage or the diagnosis of various neurological disorders. Having dementia results in cognitive changes such as difficulty with problem-solving, socializing, and memory loss, as well as psychological changes, affecting one’s personality and mental state. Known progressive dementias present in Parkinson’s and Alzheimer’s disease include Alzheimer’s dementia, vascular dementia, and Lewy body dementia. Risk factors for dementia include age, cardiovascular health, psychiatric disorders, as well as diet and exercise. [9]. Acknowledging what is known to lead to the development of dementia is crucial for uncovering whether use of a particular drug like benzodiazepines will have the same effect.  

Numerous independent studies researching the connection between benzodiazepines and dementia have made various conclusions with their collected data. Consequently, meta-analysis studies were conducted in the years following to detect trends among these case-controlled and cohort studies. Here, several factors were recognized to have influenced the diagnosis of dementia instead of the use of benzodiazepines. To clarify, if one is treating their insomnia, anxiety, or depression, with benzodiazepines, these mental illnesses are more likely responsible for their dementia, not their benzodiazepine use [3][2]. The side-effects of benzodiazepines may also cause a dementia-like condition, which can be reversible with proper withdrawal of the drug [8]. Figure 2 shows that by excluding these variables, erroneous relationships, as indicated by dashed lines, between benzodiazepine use and dementia are made [4]. With so many influences involved, it is difficult to determine any causal relationship between long-term benzodiazepine use and the development of dementia. 

 

Conclusion

Benzodiazepines are still prescribed today, just with greater caution when determining doses and the duration of treatment. A greater awareness of these drugs in the medical field can further research and the development of less addictive alternatives. To elaborate, current research has been using the effects of benzodiazepines to study the brain for treating certain neurological disorders. For example, specific benzodiazepine receptors that are responsible for a decline in memory, such as the alpha-5 GABAA receptor, could be targeted to lessen the effects of dementia [10]. Alternatives like SSRIs and SNRIs can be improved to reduce side-effects and increase efficacy, so they can be prescribed for cases that would otherwise require benzodiazepines. On the other hand, benzodiazepines can be experimented with in the future so they provide fast-acting effects without a high risk of dependence. 

Studying the mechanisms through which benzodiazepines operate could shed light on how memory is lost and give rise to alternative treatment for those with dementia [10]. Furthermore, these investigations on the possible connections between benzodiazepines and dementia ultimately show that there are multiple factors other than drug use that can lead to the development of certain illnesses. Accounting for these influences will allow for more accurate diagnoses and the increased reporting of conditions that need attention.


References


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  2. He, Qian et al. (26/10/2018) Risk of Dementia in Long-Term Benzodiazepine Users: Evidence from Meta-Analysis of Observational Studies. Journal of Clinical Neurology. 19(8): 883-894 doi: 10.3988/jcn.2019.15.1.9. Retrieved; 15/03/2020

  3. Richardson, Kathryn et al. (27/03/2019). History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study. American Journal of Epidemiology. https://academic.oup.com/aje/article/188/7/1228/5421030. Retrieved; 17/03/2019

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  8. Chatterjee, Rhitu. (25/01/2019). Steep Climb in Benzodiazepine Prescribing Traced to Primary Care Providers. NPR. https://www.npr.org/sections/health-shots/2019/01/25/688287824/steep-climb-in-benzodiazepine-prescribing-by-primary-care-doctors. Retrieved; 22/03/2020

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  10. Ettcheto, Miren et al. Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer’s Disease Dementia. (08/01/2020). Frontiers in Aging Neuroscience. 11: 344. doi: 10.3389/fnagi.2019.00344. Retrieved 17/03/2020

Kaitlyn Ramesh

Kaitlyn Ramesh


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