Funded by the Alzheimer's Society in the UK, new research (led by the University of East Anglia in Norwich, England) has seemingly flagged a warning that notes potential for increased risk of the development of dementia in individuals using certain anticholinergic medications.
Impaired brain function which causes memory loss (forgetfulness) and impaired judgement can become emotionally distressing for both the person experiencing it and their loved ones. For those on anticholinergic medications for the treatment of health issues like depression, Parkinson’s disease and urinary incontinence / bladder problems, news that the drugs they’ve come to rely on as chronic therapy may be linked to such a troubling medical condition might be a little disconcerting.
What are anticholinergic drugs?
Anticholinergic medications are a class of drug that act as a blocking agent for the neurotransmitter, acetylcholine (this neurotransmitter works within the central and peripheral nervous systems, and plays a role in attention, arousal, memory and motivation, and activation of the muscles in these respective systems). Chemicals made and released by nerves in the brain (neurotransmitters) typically travel to nearby nerves, muscles and cells, and attach themselves to receptors. Here, stimulation or activity inhibition can take place causing various physical problems and tissue dysfunction.
Uses of these types of medications are fairly broad, commonly prescribed to help alleviate symptoms associated with medical conditions troubled by muscle contraction and relaxation function.
Conditions and symptoms for which these medications may be prescribed include an overactive bladder / urinary incontinence, muscle spasms, gastrointestinal troubles (like cramps), diarrhoea, breathing difficulties, as well as mood and movement disorders (like depression and Parkinson’s disease). Anticholinergic medications which also include antihistamines are also available over-the-counter for those with seasonal allergies, like hay fever.
This class of medication is capable of decreasing muscle activity in the gut, and thereby reducing the production of urine, tears, saliva, digestive juices and perspiration. This medication class is also effective for balancing the production of dopamine, an essential component for improving problems with mood, memory, motivation, contentment / gratification, problem solving and movement (in those experiencing issues with range of motion).
Antidepressant, urologic and Parkinson’s disease medications linked to increased dementia risk
Approved by the Independent Scientific Advisory Committee for Clinical Practice Research Datalink (CPRD) – an English NHS observational data and interventional research service – the research team responsible for the latest published paper conducted a case-control study that reassessed some already known factors regarding anticholinergic medications:
- Anticholinergic medications have already been associated with short-term cognitive impairments in users (including difficulties with maintaining attention / concentration and reaction times).
- The already reported associations with cognitive impairment and development of dementia with extended therapy use.
The team of researchers found that some medications within this class can be associated with an elevated dementia risk, but not necessarily all. Those being treated with anticholinergic drugs for antidepressant purposes, as well bladder (urological) and Parkinson’s symptom relief are thought to be most at risk. Those using anticholinergics to treat gastrointestinal or respiratory conditions, as well as allergies like hay fever, do not appear to be at as high a risk.
Elevations in risk factors may mean that medical professionals might need to re-think therapeutic options when it comes to prescription treatment. As with all treatment strategies, assessing the various risks over benefits is something medical doctors do before handing over a prescription. The findings of this new study may merely mean that doctors have another risk factor to add to their list of considerations when weighing therapy benefits against possible problems that may or may not occur in a patient.
Study objectives - Spotlighting long-term effects associated with dementia development
Since the association between anticholinergic drugs and dementia has been established with short-term period use and potentially with long-term use too, the research team aimed to identify a level of exposure risk and the duration (of drug use) between different classes of anticholinergic medications in relation to dementia development down the line.
As a condition, dementia is just one of many global public health priorities. For someone diagnosed with the condition, a number of neurodegenerative processes occur causing irreversible cognitive dysfunction and distressing symptoms. The impact of dementia symptoms on an affected person’s day-to-day lifestyle intensifies over time and gradually impairs the ability to lead a fully functional and independent life. Currently, there are no treatment therapies available that can reverse the neurodegenerative effects of the disease.
In recent years, incidences of dementia appear to have declined somewhat, which suggests that environmental changes and lifestyle improvements may be having a positive effect on the overall prevalence of the condition. Reducing all risk factors as much as possible is still a high priority, especially when it comes to the middle aged and senior populations who are prone to dementia development, and typically take multiple medications as part of an overall therapy treatment solution for various ailments.
The use of anticholinergic medications in the treatment of diagnosed dementia or in seniors (in general, especially if frail) is not general practice. The depth of the adverse effects that extended use may have, in any patient, of any age, is not considered a very well understood area of therapy. Anticholinergic medications are used by many older adults, however, and a growing number of studies of late have pointed to a potential dementia risk. High dosages of the therapeutic drug may have a definitive influence, as one study found. Another did not determine a distinctive risk. (1) As such, further research is certainly required in this area so as to identify the specific mechanisms associated with increased risk. Is it the action of the medication itself or do underlying medical conditions play a role? There are certainly specifics that require a little more clarity, and this new study has seemingly attempted to start figuring the details out.
This team of researchers published their study objectives and findings in The British Medical Journal on 25 April 2018. (2) As a case-control study, the team selected patient participants (diagnosed with dementia) from the UK’s CPRD to serve as case participants, comparing their prescriptions for anticholinergic medications between 4 and 20 years prior to being diagnosed. A control group of patient participants without dementia were used for comparative purposes. The CPRD contains medical information of patients supplied by general practices in the UK.
The study made use of 40 770 patient participants who were diagnosed with dementia between April 2006 and July 2015, and 283 933 individuals without the condition for the control group. All participants were between the ages of 65 and 99. Approximately 78% of the selected patients were from general physician records in England. The remainder consisted of records from Scotland (9%), Wales (9%) and Northern Ireland (3%). About 63% of the participants were female with the average overall age being 83 when patients were recorded as being under observation for dementia diagnosis.
As part of the overall objective to identify the level of exposure risk and duration, the research team had three approaches in mind:
- Determine an estimation of association between chronic medication use (before diagnosis) and the subsequent dementia diagnosis (keeping any related confounding factors in mind).
- Identify any observed effects associated with specific medications used.
- Test the associations, taking into account the amount of exposure (from the different sub-classes of anticholinergic medications) and the time period before an eventual diagnosis of dementia was made.
How was the study conducted?
Participation criteria
The participant data used from the CPRD primary care records details information such as gender, age, ethnicity, some lifestyle factors, as well as potential referrals, diagnostic notes, prescriptions and therapy recommendations made by a general practitioner and, if relevant, a referred physician. Information in these primary care records is listed anonymously when made available for research purposes. The CPRD holds records for more than 11.3 million individuals in the UK from between 600 and 700 primary care medical practices.
The reason primary care records were selected is because this is where the majority of healthcare information for the general public is held. From here, any necessary key secondary care information is easier to determine.
The research team carefully selected their study participants from these records. The time periods and related factors of participants was also key – exposure to anticholinergic medications can make for challenging estimations in relation to their effect on individuals. Thus, the team ensured that information from selected patient participants all had at least 6 years’ worth of primary care information, allowing for at least 4 years before a dementia diagnosis was made and no less than 1 year of exposure to anticholinergic medications used for treatment. The research team refined their list by excluding certain participants who were also under treatment for conditions like multiple sclerosis, motor neuron disease, Down’s syndrome, HIV/AIDS or were noted to have battled with alcohol abuse before a dementia diagnosis was made.
Study monitors
The research team enlisted the assistance of 4 volunteers from the Alzheimer’s Society Research network. All of the representatives had experience in caring for patients with dementia and could help contribute by sharing relevant information regarding drug activity and the possible cognitive decline of patients. During the study period, volunteers met with the team every 6 months to discuss research progress.
Quantifying anticholinergic effects
The effects of anticholinergic drug exposure are typically classified according to ACB (Anticholinergic Cognitive Burden) scales, which are developed based on expert consensus and literary reviews and are periodically updated. The research team made use of the 2012 update of the ACB scale as this was most relevant during their period of assessment.
The scales are intended as a measure of potential anticholinergic activity effects. Based on these effects associated with known anticholinergic medications, individual drugs are scored between 1 and 3.
A score of 1 is generally given if an effect is noted via laboratory testing procedures (without clinically relevant cognitive symptoms). Scores 2 and 3 are assigned if both testing and clinically evident effects are noted. A score of 2 is based on blood-brain penetration effects. A drug that appears to induce delirium (as well as shows signs of blood-brain penetration effects) will be given a score of 3 and is assumed to have 3 times the anticholinergic activity of those with a score of 1. During treatment, physicians aim to make use of medications with the lowest ACB score possible in order to reduce the overall anticholinergic cognitive burden on a patient (i.e. the drug load a patient’s body will have to deal with). Those medications that are not listed as 1, 2, or 3 are given a score of 0.
The research team allocated a score of 1 to antihistamine, loop and thiazide diuretic anticholinergic drug classes, and 3 to tricyclic antidepressants.
They made use of ACB scores (calculating an average among the sum of all listed drug classes being used) and the number of defined daily doses per patient (as was noted in their records). The team also categorised the different drug classes (according to primary indications for use) being used:
- Analgesics
- Antidepressant
- Antipsychotic
- Cardiovascular
- Gastrointestinal
- Antiparkinson
- Urological
- Respiratory
- Other
The team then went on to determine drug exposure patterns in the case study group, making comparisons with the number of defined daily doses and the listed ACB scores. The team analysed data using Stata version 14 software, repeating a primary analysis for each set 3 times. The team then conducted a final sensitivity analysis by making use of the anticholinergic drug scale (ADS) in place of the ACB scale for comparison. This scale was also developed to help classify the degree of drug activity – scores are given between 0 and 3. No notable anticholinergic effects are scored as 0 and marked effects are classified as 3. Literature reviews and expert consensus also contribute to this scale.
What did the study determine?
In a nutshell, the research team associated dementia cases with the higher end of average ACB scores (and larger quantity dosages). Drug classes used for gastrointestinal purposes did not appear to be associated with a dementia diagnosis / later dementia incidence (or the increased risk of), even with a high ACB score in medications used over a long period of time. Drug exposure to medications used as antidepressants or for urological and Antiparkinson treatment appeared to carry the greatest risk of developing dementia, even in patients using the drugs between 15 and 20 years before a diagnosis was made. The team determined an odds ratio of 1.19. Drugs for antidepressant purposes (with ACB scores of 3 or even 1) were consistently determined as having a role in increasing dementia risk. Any drug prescribed with an ACB score of 3 was determined as having an odds ratio of 1.17.
During the period of study, the team determined that 35% of the case participants and 30% of the control group had been prescribed at least 1 anticholinergic drug with an ACB score of 3. The number of drug prescriptions written (for drugs with an ACB score of 3) during this time period totalled 1 793 505. The most commonly prescribed sub-classes and which appeared most consistent with increased dementia risk were:
Antidepressant drug class prescriptions
- Amitriptyline (Elavil) – 29%
- Dosulepin (Dothiepin) – 16%
- Paroxetine (Paxil) – 8%
Urological drug class prescriptions
- Oxybutynin (Ditropan) – 7%
- Tolterodine (Detrol) – 7%
These drugs are considered to have ‘definite anticholinergic activity’ (or effects on the brain) which can persist for up to 20 years following exposure to the medication. This definite activity is what the researchers suggest contributes to the development of dementia as a degenerative condition.
Drugs with an ACB score of 2 were prescribed in 3.5% of the case group and 2.8% of the control group participants. The most popular drug of choice was carbamazepine (Carbatrol or Teril which are often prescribed to treat neuropathic pain) totalling 87% of these prescriptions. At least 89% of all case group participants and 87% of the control group had at least one prescription for a drug with an ACB score of 1 – about 63% of these prescribed medications were commonly used cardiovascular class drugs.
The team determined that dementia development risk increased with higher anticholinergic burden scores and higher quantities of the drug. Drugs with higher scores (particularly 3) for urological, Parkinson’s disease and depression management consistently appeared to be the most concerning. The use of drugs (including cumulative use) with an ACB score of 1 did not appear to increase risk, with antidepressant classes being the exception. Such drugs with this score are generally viewed as ‘possibly anticholinergic’ (albeit with a lower activity / effect). Medications prescribed for antispasmodic, antihistamine or antipsychotic effect, even with an ACB score of 3 did not appear conclusively relevant in relation to dementia development following extensive use.
The comparisons between ACB scores and ADS also appeared consistent when it came to antidepressant, urological and Anti-Parkinson drug exposure.
Study limitations
The findings of this study are potentially significant and should urge further investigation. It is the first study to determine individual anticholinergic effect estimations using the primary care database of population representatives (using those with genuine cases of dementia) on a large scale, along with a longer patient history. Detailed analysis of different drugs within the medication class covered up to 20 years’ worth of data. This study also looked at individual drug classes, something which has not been done previously to the same scale. There were study limitations, which should influence any further research conducted in order to better clarify odd spots of uncertainty.
One area the research team acknowledge as a potential limitation stems from the known fact that many instances of dementia are under diagnosed or never diagnosed at all. The team acknowledge the possibility that some of their control group could have had signs of early cognitive impairment or undiagnosed dementia which their recorded information may not have provided clues to. The team worked with records and not actual human beings, so without being able to physically observe a patient in person, the team cannot be 100% sure in this regard.
Another relates to use of drugs for antihistamine purposes, which can be obtained over-the-counter, as well as via prescription. It is difficult to gain a complete estimation of anticholinergic activity in this regard as not all of these drugs are recorded in the primary care database. Whether patients maintained therapy according to prescribed dosages of recommended drugs overall is also difficult to determine from the records used. The team can see what was recommended, not the physical implementation of therapy by a patient – it is widely known that some patients alter dosages of medication on their own without a doctor’s consent.
There could also be unknown confounding factors not mentioned in the data that make certain aspects of the study unmeasurable. Some of these could be demographic details not stipulated or lifestyle factors (including smoking habits and alcohol consumption) which may influence the development of dementia.
The research team do acknowledge that the precise assessment of drug activity (i.e. the anticholinergic effect) for each and every sub-class of the drug is difficult using the various scales available (as the way in which drugs are classified can differ somewhat) but feel that their comparisons between the ADS and the ACB scale was consistent enough to provide a reliable starting point. The team also feel that their findings, although determined using UK based participants, can potentially be applied to other populations in developed countries.
How should these results be interpreted going forward?
For clinicians and drug policymakers, this research further supports previous small-scale studies and is worth taking note of. The team feel that although the odds ratios they determined are not overwhelming, the incidence of dementia in populations and the drug associations identified in their study warrants caution when prescribing these medications. As the study points out, it is estimated that an average person between the ages of 65 and 70 has a 10% increased risk of developing dementia. With the usage of anticholinergic medications, this could increase to around 13%.
Alzheimer’s Society’s Chief Policy and Research Officer, Dr Doug Brown, further highlights dementia development risk, pointing out that there have been no newly developed treatments for the condition in roughly 15 years. This means that prevention is a serious consideration and any increase in risk must not be disregarded. Along with ongoing research efforts, Dr Brown makes the point that in order to prevent this condition from developing, better understanding of what raises risk is urgently needed. Research helps with this.
The team advise clinicians to be vigilant when prescribing anticholinergics for certain conditions, keeping medication options and their known effects and risk factors in mind. It should be considered that dementia may be a risk factor up to 20 years following treatment (especially with higher ACB score drugs) for conditions like urinary incontinence, for instance. Cautionary use of anticholinergic drugs in older individuals, especially those who are frail or who have multiple health concerns requiring treatment is already high on the agenda for physicians to take into consideration before issuing a prescription.
Dr Brown appears in agreement with the research team’s findings – “Current guidelines for doctors say that anticholinergic drugs should be avoided for frail older people because of their impact on memory and thinking, but doctors should consider these new findings for all over-65s as long-term use could raise the risk of dementia.”
For patients, this increased risk could be significant and should be acknowledged. The team pose the idea that perhaps anticholinergic medications serve as markers of prodromal / preceding dementia symptoms. Different class groups of these drugs may be capable of crossing the blood-brain barrier, thus explaining the potential for increased risk – not just over short-term periods, but with long-term use too.
It is fair to assume that a sizable portion of the population are prescribed anticholinergic medications at least once in their lifetimes. The real danger for those who require such medications for chronic condition treatment (especially depression, Parkinson’s disease and even chronic urological problems), is increased long-term exposure. The team feel that this must be taken into consideration, especially from the patient’s perspective. The long-term risk of possible cognitive effects must, in the research team’s opinion, be considered when physicians make risk/benefit analyses.
The team feel that any future research must take into consideration other potentially harming factors as a result of differential drug effects. More detailed comparisons of cumulative drug exposure (dosages and different drug classes) over extended time periods and different mechanisms of drug actions relating to individual drug classes are some of the aspects future research could factor in to study designs. Cognitive and neuropathological effects as they compare with specific medication classes, as a result of long-term use can definitely be studied further.
This team of researchers did not aim to determine the association between anticholinergic medications and dementia development, linking the drugs as a direct cause and do not claim outright that these medications cause dementia, but there is a link, and this warrants further study. Future research could potentially concentrate on this to see if indeed a direct causal link could be possible.
What this research does show is dementia development risk may be influenced by a specific drug class sometimes used for the treatment of very early signs of dementia (which can also display in Alzheimer’s patients). Further research looking at the mechanics of the different anticholinergic drug classes versus the specific anticholinergic effects may provide better clarity.
In the meantime, what can be done for those already using anticholinergic drugs?
For those using anticholinergic medications, the finding of this study may be somewhat worrying, especially when side-effects of these medications already indicate possible short-term confusion and an increased risk of falls.
Those taking multiple medications, especially seniors, may also wish to take note of this study, especially if one or more of their medication therapies fall into the anticholinergic class. It is becoming increasingly common for older individuals to be taking at least 5 different medications at any given time to manage chronic or persistent health troubles. If it turns out that the risks outweigh the benefits, where does that leave patients?
One option patients and their prescribing physicians could look at proactively doing is ‘de-prescribing’ certain medications especially where multiple drugs are being used. In many instances, there are alternative therapies which can be considered. For instance, not all anti-depressant medications are classed as anticholinergics, so alternatives can be considered in order to lessen risk wherever possible.
The team of researchers advise ‘de-prescription’ and a reassessment of benefits and risks, especially in relation to treatment of the conditions they determined as at higher risk. No patient, however, should panic and stop taking their medications without the express consent of their physician. Together with a physician, both doctor and patient can reassess a particular health condition and make adjustments as necessary for optimum long-term treatment. While these medications have not been determined as having a direct causal link to dementia development, patients should discuss any concerns with their treating doctors, taking appropriate steps to avoid unnecessary treatment hiccups and side-effects.
The findings of this study will certainly be looked at with care, both from a physician’s point of view and those of healthcare regulatory bodies. Patient safety is a high priority, and should further research support the findings of this study and those conducted previously, guidelines will certainly be adjusted accordingly.
References:
1. US National Library of Medicine - National Institutes of Health. July 2016. Anticholinergic medication use and dementia: latest evidence and clinical implications: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014048/ [Accessed 02.05.2018]
2. The British Medical Journal (BMJ). 25 April 2018. Anticholinergic drugs and risk of dementia: case-control study: https://www.bmj.com/content/361/bmj.k1315 [Accessed 02.05.2018]