Sunday, 5 April 2015

ClinicSpeak: anticholinergics increase risk of dementia

Is it time to bin your centrally-acting anticholinergics? #ClinicSpeak #MSBlog #MSResearch

"Neurologists prescribe drugs with anticholinergic effects like smarties (a coloured sugar-coated chocolate sweet) to MSers with depression, insomnia, central and peripheral pain syndromes, allergies, and urinary urgency and frequency. The main classes of drugs are tricyclic antidepressants, antihistamines and antimuscarinic drugs for bladder problems. We prescribe these drugs knowing that they result in cognitive impairment. We have always thought these effects are reversible. Maybe they are not. The population-based study below shows that the cumulative anticholinergic exposure, or dose, is strongly associated with the development of dementia and in particular Alzheimer's disease. The question is does this apply to MS?"

"MS is a dementing illness, albeit a preventable dementia. Does anticholinergic drugs speed up the dementing process in MS?"

"For the reasons above I have had a long-running campaign against the use of older generation anticholinergics for MS-related bladder dysfunction, for example oxybutynin. The older drugs cross the blood-brain-barrier and have been shown to impair memory and cognitive function. The newer generation anticholinergic bladder drugs (tolterodine, solifenacin, etc.) are designed not to cross the blood-brain-barrier and are hence associated with less, or very little, cognitive problems. The tricyclics antidepressants (e.g. amitriptyline), are a harder class of drug to deal with; we use 
tricyclics because we want their central effects to modulate pain pathways and to use their sedative effects to help MSers sleep. But at what cost? Since the paper below has come out I am starting to backtrack on using tricyclics and have started prescribing Duloxetine more, which works well for central pain syndromes, but lacks anticholinergic effects. Duloxetine is also much less sedating than the tricyclics, but that can be helpful."

"You are probably aware that anticholinergic drugs also exacerbate constipation, cause dryness of the mouth and are associated with increased falls. On balance therefore it seems MSers would be much better off with a lower central anticholinergic drug load. What do you think? If you are on a drug with central anticholinergic effects you should ask you neurologist or MS clinical nurse specialist if the drug(s) is/are really necessary."

Related blog posts to read: oxybutynin worsens MS-related cognitive impairment; lower urinary tract infections; managing your bladder problems; urinary problems in CISers; MS dementia

Gray et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015 Mar 1;175(3):401-7. doi: 10.1001/jamainternmed.2014.7663.

IMPORTANCE: Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.

OBJECTIVE: To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.

DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated healthcare delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.

EXPOSURES: Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.

MAIN OUTCOMES AND MEASURES: Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.

RESULTS: The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.

CONCLUSIONS AND RELEVANCE: Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.


  1. This is worrying. I have taken amitriptyline mainly for depression and thought that because the dose was quite small, it was safe long-term. Time to ask the neuro?

  2. pROF g, even you must pour scorn over Novartis' actions (

    Big Pharma is anti-society.

    1. Re: "pROF g, even you must pour scorn over Novartis' actions ("

      We have posted on this issue before:

    2. Re: "Big Pharma is anti-society."

      I am not sure about this. When it comes to developing new drugs Big Pharma are really the only show in town. Without Big Pharma there would be no new drugs. What you have to realise is that Big Pharma are almost all publicly listed companies with a brief to make money for their shareholders. Some of the largest shareholders of Pharma stock are pension funds; without Pharma profits and large dividends the pension funds can't pay pensions, etc. At a macro-economic level things could be viewed differently, therefore I am not sure Big Pharma is anti-society they are simply another cog in the complex machine that make society work.

      You need to be aware that there are EU laws that make off-label prescribing for a specific indication illegal, when there are licensed drugs available for that indication. I think Novartis and other Pharma companies are simply looking after their shareholders interests.

      If we want things to change we need a Big Pharma Alternative (BPA); we have been proposing this for some years now. The problem is a BPA requires a political solution and our politicians don't seem to be engaged enough to find a solution.

  3. Thank you for this post. I might have been prescribed such drugs for bladder issues, but I resolved the matter with herbals and pelvic floor exercises. Boy, am I glad about that after reading this.

  4. I read that you are now using Duloxetine instead of Amitriptyline.Is Duloxetine as effective as Amitriptyline?

    I have been taking 30mg of Amitriptyline every night for quite a few years. I am now reducing my intake by 10mg per month and started a few days ago. Already I'm finding it harder to drop of to sleep each night. I'm sure the situation will get worse.

    Do I have to completely stop Amitriptyline before switching to Duloxetine?


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