By Nicole Coniglio, MSN, APRN, PMHNP-BC, ACNP-BC
Psych360 knows the importance of, and always recommends, gradual dose reduction (GDR) for their patients when the time comes to eliminate medications or test for their necessity. GDR is the gradual tapering of dosage a patient is on while monitoring any symptoms, side effects, or conditions they may have. This way, the provider and patient can determine if the patient’s symptoms can be managed by a lower dosage, or even without the medication without risking the patient facing withdrawal or losing medication they need.
This can be especially helpful with medications such as benzodiazepines, which are commonly used to treat conditions such as Alzheimer’s disease or dementia. With all of the current medical discussion about the potential help vs. harm that both the disease management and/or the disease itself could be causing, it’s helpful to know just how much of the medication the patient actually needs.
Benzodiazepines and Anxiolytics
An anxiolytic is a therapy or medication that assists a patient with anxiety, though there are variations on its methods of doing so. Some types of anxiolytics are antidepressants, anticonvulsants, and antihistamines. The most well-known type of anxiolytic, however, would be benzodiazepines, or BDZRs.
Benzodiazepines are the medications most commonly used to treat anxiety, but can also be used for other symptoms or ailments. They are effective in treating seizures and insomnia and can be used for withdrawal, general anesthesia, nausea, sedation, and depression. They tend to have general side effects such as dizziness, sedation, unsteadiness, and weakness, which goes hand in hand with the medications intention of easing and sedating the patient. Some of the better-known benzodiazepines are Valium (diazepam), Ativan (lorazepam), and Xanax (alprazolam). They are more commonly prescribed to women than to men according to an analysis done in Germany, published in 2019. They also discovered that BZDRs are prescribed more prolifically in nursing homes than in communities or to those who live at home:
Among the 395 study participants, 49 patients (12.4%) were treated with BZDR at least once over a period of three months before the interview. Of these, the majority were women (71.4%, n=35) similar to the proportion of female patients among those not receiving BZDR (67.6%, n=234). On average, BZDR users were not significantly older than non-users (80.0±9.3, median: 84.0 vs. 78.7±8.5, median: 80.0). With regards to the respective substances, the following were most often prescribed: lorazepam (42.9%, n=21; half-life: 9–19 h), oxazepam (22.4%, n=11; half-life: 4–15 h), diazepam (14.3%, n=7; half-life: 30–56 h), and zopiclone (12.2%, n=6; half-life: 2–6 h).
Patients treated with BZDR significantly differed from those not medicated with BZDR regarding their residential status. BZDR were more often prescribed in nursing home inhabitants compared to community-dwelling participants (p<0.001). In total, BZDR were used in 22.0% (n=27) of the nursing home inhabitants compared to 8.1% (n=22) of the patients living in their own home environment. Altogether, 66.2% (n=262) of all participants were seen by neurologists or psychiatrists during the study period. However, BZDR were significantly more often prescribed among dementia patients who were not treated by a neuropsychiatric specialist (63.3%, n=31 vs. 36.7%, n=18; p<0.001).
Anxiety May Fuel Dementia or Alzheimer’s Disease
BZDRs and anxiolytics are commonly prescribed for dementia and Alzheimer’s disease because one of their most prevalent symptoms is anxiety. While it feels relatively obvious that dementia and its variants would be anxiety-inducing due to the memory loss, inability to communicate effectively, difficulty with judgment and reasoning, and visual perception issues,any one of those symptoms on their own could cause enough anxiety to be medicated.
However, studies are finding that anxiety may not only be a symptom of dementia, but it could also be a cause. A study published in the British Journal of Psychiatry found that anxiety is a risk factor for both Alzheimer’s disease and Vascular Dementia. Another study published to Maturitas found that “individuals with anxiety showed a statistically significant 29% increased risk of dementia compared to individuals without anxiety,” concluding:
this meta-analysis of prospective cohort studies suggests that anxiety significantly increases the risk of dementia. Considering the high prevalence of anxiety in older populations worldwide, our results suggest that treating or preventing anxiety may help to reduce the incidence and prevalence of dementia, and the heavy burden that this condition brings.
There is, however, a slightly different opinion on the connection between early anxiety and later dementia. Scientists at the University of California in San Francisco (UCSF) and the Brazilian BioBank for Aging Studies (BBAS) worked together to compare results of postmortem brain tissue to detailed interviews with people who knew the deceased and their symptoms. They have reason to believe that anxiety, sleep loss, and other similar symptoms are not causes or even risk factors of dementia or Alzheimer’s disease. Instead, they are symptoms, and the physical manifestation of Alzheimer’s disease takes hold long before the psychiatric symptoms first appear. Dr. Lea T. Grinberg, Associate Professor of neurology at UCSF and the primary investigator, stated that this study “suggests these people with neuropsychiatric symptoms are not at risk of developing Alzheimer’s disease—they already have it.” While this needs further studying, this could help doctors catch the disease far sooner and potentially cut back on these symptoms for patients.
While this line of questioning is still in early stages, it is well documented that anxiety is undoubtedly a part of the disease’s progress. If not as a cause, as a risk factor; if not as a risk factor as an early warning system for worse symptoms to come. Now that we know this, we need to work to reduce anxiety in seniors to reduce the risk of Alzheimer’s disease and improve the quality of life for patients who already have the disease.
Do BZDRs Increase the Risk of Alzheimer-Type Dementia?
There is a general controversy about benzodiazepines and their risk versus reward. Many recent studies have proclaimed that the use of BZDRs to treat anxiety and other similar symptoms or conditions could create a greater risk of Alzheimer’s or other dementia types. The British Medical Journal (BMJ), published a study on this very topic and discovered that their work reinforced “the suspicion of an increased risk of Alzheimer type dementia among benzodiazepine users, particularly long-term users” and showed that the “use of benzodiazepines at any time was significantly associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69)”.
Psychology Today takes these risks into account when considering the treatment of depression and anxiety in dementia patients. They recommend therapy and repetitive therapeutic acts such as meditation, aerobic exercise, and relaxation therapies to assist the patient manage their anxiety or depression by improving their mood and keeping to a schedule. They discuss how to help with irritability, in addition to pharmacological therapies such as escitalopram or sertraline to manage symptoms; however, they recommend minimal doses of these to minimize side effects and thoroughly recommend GDR should the time come to discontinue them. However, they explicitly state:
Many antidepressants and anxiolytics can cause cognitive impairment. We try hard to stay away from those classes of medications. For example, we never prescribe a benzodiazepine for individuals who already have cognitive impairment at baseline.
While this seems to be a pretty simple connection, the results may not be as cut and dry as they seem. One must always take a step back and ask if the numbers are actually related— Are they causing one another? Merely a coincidence? Or is another, unseen factor the cause of the correlation? Janna Lawrence discusses this when comparing the results of a study done to determine the connection between benzodiazepine and Alzheimer’s disease. The data showed that those who had been exposed to BZDRs for more than three months showed an increased risk of Alzheimer’s disease:
Overall, 49.8% of patients with Alzheimer’s had ever used benzodiazepines, compared with 40.0% without Alzheimer’s. Patients who had ever been exposed to benzodiazepines had an increased risk of Alzheimer’s disease (adjusted odds ratio 1.50, 95% confidence interval, 1.36–1.69). When this figure is broken down, cumulative exposure of up to three months was not associated with an increased risk (OR 1.09, 95% CI, 0.92–1.28). Use of benzodiazepines for longer than this was found to increase the association with Alzheimer’s; between three to six months (OR 1.32, 95% CI, 1.01–1.74) and for longer than six months (OR 1.84, 95% CI, 1.62–2.08) and the association was stronger for longer-acting benzodiazepines (OR 1.70, 95% CI, 1.46–1.98) compared with short-acting benzodiazepines (OR 1.43, 95% CI, 1.27–1.61).
David Taylor, director of pharmacy and pathology at King’s Health Partners clarified the issue Lawrence was discussing by asking, “Do benzodiazepines cause or hasten the onset of Alzheimer’s or do people later diagnosed with Alzheimer’s use benzodiazepines to treat early symptoms associated with the condition? We can never really know”.
Not everyone is in full agreement about whether or not BZDRs cause or are a risk factor for Alzheimer’s disease, or if there is even a correlation. As a matter of fact, a study published in Drug Safety found the exact opposite. According to their results, “benzodiazepine use was not associated with an increased risk of developing AD [Alzheimer’s disease] or VaD [Vascular Dementia]”:
The aOR (95 % CI) of developing AD for those who started benzodiazepines <1 year before diagnosis was 2.20 (1.91–2.53), and fell to the null for those who started between 2 and <3 years before [aOR 0.99 (0.84–1.17)]. The aOR (95 % CI) of developing VaD for those who started benzodiazepines <1 year before diagnosis was 3.30 (2.78–3.92), and fell close to the null for those who started between 3 and <4 years before [aOR 1.16 (0.96–1.40)]. After accounting for benzodiazepine use initiated during this prodromal phase, long-term use of benzodiazepines was not associated with an increased risk of developing AD [aOR 0.69 (0.57–0.85)] or VaD [aOR 1.11 (0.85–1.45)].
Science lends its support to both sides. Benzodiazepines may be increasing the risk of Alzheimer’s disease, or it may only be treating the symptoms that come along with it. Nevertheless, BZDRs do come with some increased health risks that do need to be taken into consideration when prescribing them to anyone, especially seniors.
Benzodiazepine Related Incidents
While the idea of BDZRs potentially causing or increasing the risk of Alzheimer’s disease is still disputable, there are other reasons many others will not prescribe them for their patients. Two such reasons are the increased danger accompanying falling and hip fractures, and the increased risk of pneumonia in BDZR using patients.
Increased Hip Fractures
A study published in Elsevier investigated the correlation between benzodiazepine use and the consequences of hip fractures, examining hospital stays and mortality rates. With their findings, found below, they concluded that cutting back on BZDR use could also cut back on the rate of hip fractures and the length of hospital stays for patients with Alzheimer’s disease:
BZDR use was associated with an increased risk of hip fracture in persons with and without AD (adjusted hazard ratio 1.4 [95% CI 1.2–1.7] and 1.6 [95% CI 1.3–1.9], respectively). BZDR use during hip fracture was associated with longer than 4-month postfracture hospital stay in persons with AD [adjusted odds ratio 1.9 (95% CI 1.3–2.8)] but not in comparison persons. One-year mortality was not associated with BZDR use during hip fracture.
But this is just one risk associated with prolific BZDR use among senior populations.
Increased Risk of Pneumonia
There have been suspicions about a connection between benzodiazepines and pneumonia risk for quite some time. But in 2017, a study was published in the Canadian Medical Association Journal (CMAJ), examining this topic for any connection. Those involved discovered that BZDRs in patients with Alzheimer’s disease were associated with an increased risk of pneumonia when set against Alzheimer’s patients using Z-drugs or not taking either type of medication.
Among 49 484 eligible participants with Alzheimer disease, 5232 taking three benzodiazepines and 3269 taking Z-drugs were matched 1:1 with those not taking these drugs. Collectively, use of benzodiazepines and Z-drugs was associated with an increased risk of pneumonia (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.05–1.42). When analyzed separately, benzodiazepine use was significantly associated with an increased risk of pneumonia (adjusted HR 1.28, 95% CI 1.07–1.54), whereas Z-drug use was not (adjusted HR 1.10, 95% CI 0.84–1.44). The risk of pneumonia was greatest within the first 30 days of benzodiazepine use (HR 2.09, 95% CI 1.26–3.48).
This risk, combined with the increased risk of hazards of fractures and everything that comes with them, could be enough to make doctors think twice before prescribing their senior patients benzodiazepines, especially those with Alzheimer’s disease. Throw on top of that the doubts about BDZRs potentially causing or contributing to Alzheimer’s disease and a doctor should really consider all alternative options first.
There have been many searches for alternate methods to handle anxiety, sleep loss, and other similar symptoms in Alzheimer’s patients. Some have looked into natural routes by testing things like Ferulago angulata, a shrub used in traditional medicine for everything from snakebites and ulcers to hemorrhoids and sedation. A study was done using this shrub for its natural sedative qualities on rats to test for anxiolytic qualities. It was discovered that:
Inhalation of F. angulata essential oil significantly exhibited anxiolytic and antidepressant‐like effects and also antioxidant potential. Furthermore, in silico studies carried out by employing molecular docking experiments pointed to the existence of strong interactions of monoterpenes from F. angulata essential oil with anxiolytic and antidepressant effects with GABAAreceptor.
This, or perhaps other natural anxiolytics, could be an option to explore further.
Another direction doctors and scientists have been investigating is the use of trazodone in Alzheimer’s patients. While trazodone is traditionally used to treat depression, a study published in the Journal of Alzheimer’s Disease tried to determine a connection between the medication, Alzheimer’s disease, and sleep. However, throughout their investigation, they found many benefits to trazodone:
Trazodone has minimal effects on muscarinic cholinergic receptors, in contrast to older anti-depressant medications. Trazodone produces a higher quality of sleep for those patients who work with the dosing than the GABA agonists (e.g., benzodiazepines), anti-cholinergics, or anti-histamines (e.g., diphenhydramine), which are widely used but impair cognitive function short-term and are now being considered as contributors to the development of dementia and AD pathology long-term.
Trazodone has a generally positive effect on sexual desire and male erectile function, but it is also known to cause priapism, an emergency condition, similar to what can be associated with medications used to treat erectile dysfunction. It is estimated that abnormal erectile function occurs in about one in 6,000 male, mostly younger, patients treated with trazodone.
Trazodone is also useful for agitation. (There are anecdotes that 12.5 mg under the tongue decreases road-rage.).
Trazodone is relatively safer than most other antidepressants in overdose situations. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200 mg.
Trazodone may also be effective as a treatment for obstructive sleep apnea with worsening hypoxemia, which could also be beneficial for cognition and AD prevention. This effect could be related to serotonin, norepinephrine, or histamine mechanisms.
If this could be a safer alternative to BDZRs, it seems worth exploring, especially with all of the positive effects.
Anxiolytics, and benzodiazepines in particular, raise many questions about risk versus reward and cause versus effect. While there are still many questions being asked about BDZRs—Are they a cause of Alzheimer’s disease? An effect of it? Do they prevent it by eliminating anxiety, a potential cause?—there is still enough debate about them to keep everything inconclusive.
Benzodiazepines certainly have their uses. They help patients. But with all of the uncertainties, doctors and medical facilities should be careful when prescribing them and taking care not to overprescribe. Records should be kept and reasons are given for these medications, and when the medications are no longer needed, GDR should be used to ensure the patient’s health and comfort.