Drugs and Dementia

Sandra Steingard, MD
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This week, JAMA Internal Medicine published online an interesting paper, “Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study.” They found that exposure to anticholinergic drugs significantly increased the risk of developing dementia. This study has important implications for those who prescribe and take psychiatric drugs but it is worthwhile describing the study in some detail before discussing those implications.

First, some context. Acetylcholine (ACh) is a neurotransmitter (a chemical that propagates a nerve signal from one cell to the next) that is found throughout the body. It is involved in gut motility, visual acuity, heart rate, and secretions. In the brain, its activity is linked to memory and movements. There are many drugs that blocked ACh receptors (the proteins that allow nerve transmission to occur). In psychiatry, anticholinergic drugs are used to combat some of the neurological effects of the neuroleptic drugs such as muscle stiffness and tremor. But there are also many drugs used to treat depression and psychosis that have anticholinergic effects.

Drugs that block the action of Ach – anticholinergics – often cause dry mouth, constipation, rapid pulse, urinary retention (difficulty emptying one’s bladder), and blurred vision. But these drugs can impair memory. What this study addressed was the extent to which these drugs are associated with a new diagnosis of dementia and also, of importance, whether individuals who discontinue these drugs remain at higher risk of developing dementia.

They evaluated adults 65 years or older who received their health care within one integrated system in Seattle. This allowed them to access records for all drugs the individuals had been prescribed for 10 years leading up to and during the study. They excluded individuals who had a prior diagnosis of dementia and they screened everyone for signs of dementia at the outset of the study and then biennially for the duration of the study. In total they followed 3434 individuals. They calculated total anticholinergic exposure in a way that took into account both the daily dose prescribed and the total number of days the dose was prescribed to determine a total standardized daily dose.

This was a careful study. To avoid what they call protopathic bias – the possibility that one of these drugs was prescribed to treat depression or insomnia that in retrospect was an early sign of dementia – they excluded from their calculations all drugs prescribed in the year prior to the onset of dementia. They statistically controlled for factors that could contribute to dementia: age, sex, smoking status, years of education, body mass index. They accounted for health care status and several specific health conditions that could impact the results – coronary heart disease, Parkinson’s disease, diabetes, stroke, hypertension, depression, and concurrent benzodiazepine use.

There were two major findings. The first is that total exposure to anticholinergic drugs increases the risk of developing dementia. But of further concern, these effects were seen even if the drugs had been stopped years before the onset of dementia.

They found that there was a dose response risk for developing dementia, i.e. those with greater exposure had an increased risk. The Hazard Ratio for those in the highest exposure group was 1.54 with a 95% confidence interval of 1.21-1.96. This means that those who had the highest exposure to the drug had a 1.5 greater likelihood of developing dementia than those who had no exposure.

This study has general implications since there are so many drugs on the market that have anticholinergic effects. In our age of increasing polypharmacy, especially as people age, this is a warning call to be judicious in our prescribing.

But the study has particular implications for psychiatry. First of all, many psychiatric drugs have anticholinergic effects. The older tricyclic antidepressants as well as some older neurolpetics were on the researchers’ list. But there were also some newer ones – paroxetine (Paxil), olanzapine (Zyprexa) and clozapine (Clozaril).

The paper is of particular interest to me because it relates to one of the very first research studies in which I participated. It was a study that tested the hypothesis that the dose of haloperidol that caused minimal neurological side effects – the neuroleptic threshold (NTH)– as measured with a simple, brief examination was also the effective dose. Going higher on the dose yielded more discomfort but no further reduction of psychotic symptoms. PET studies have supported this hypothesis: 70% blockade of dopamine receptors yields an anti-psychotic effect and 80% yields significant neurological side effects. Anticholinergic drugs are used to reduce the neurologic symptoms. But they should never be needed. If someone has these symptoms the thing to do is to lower the dose not add another drug. If the person still has psychotic symptoms on the lower dose, increasing it is not likely to yield any further improvement.

The NTH paper was published just before the newer neuroleptics were coming to the market. Whereas in the late 80’s, academic psychiatrists were talking about moderating dose, by the late 90’s everyone was talking about how safe the newer drugs were. Polypharmacy – once shunned in academic circles – came back into favor. Most psychiatrists in practice today were trained in the 1990’s or 2000’s.

Beyond that, my one gripe with this paper is that the list of drugs with anti-cholinergic effects did not seem complete. Another site, which appears to do a good job of tracking drugs’ anticholinergic burden, includes many more psychiatric drugs which are in common use. A recent study, reported the risk of dementia among people diagnosed with schizophrenia to be about double the risk of the general population. We know that many people are being exposed to psychiatric drugs at very young ages and then are often on them for many years. Although there is much discussion in the psychiatric literature about cognitive impairment in people who are diagnosed with schizophrenia it is most often discussed as a result of the psychiatric disorder not of the drugs the person is taking.

I sometimes wonder how we know what we know. For instance, a psychiatrist goes through extensive training and ends up with a sense of having a general grasp on the field. But no one can read everything that has been published. Much of our learning is still in the apprentice mode – we learn from those around us. Most residents never learn about the neuroleptic threshold. And many emerge with the belief that the cognitive impairments associated with schizophrenia are due to the “disease” rather than the drugs we give.

I have come back to this theme again and again. This is not an anti-drug discussion. It is a respect-the-drug discussion. We need to use these drugs with caution. Dose matters. Length of time a person is on them matters. Polypharmacy matters.

Acknowledgment: I want to thank the always insightful and incisive Nev Jones for discussing this paper with me and directing me to some helpful papers and websites pertinent to this topic.

 

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46 COMMENTS

  1. This was a study that caught the attention of a lot of people I know who aren’t particularly interested in issues related to psychiatry…mainly because of many articles highlighting Benadryl/dementia. Perhaps it will help people to further delve into the complications of long term use of anticholinergics.

    But I was not aware of that site that you link to that shows the breakdown in anticholinergic properties of most psych drugs. In the category that shows strong anticholinergics effects (scoring a 3), that is quite a list that includes most of the “1st generation” antipsychotics but also the very commonly prescribed seroquel and Zyprexa.

    Sadly, I assume this won’t have a great effect on prescribing patterns, but I wonder why. Will the APA try to dismiss these findings? Simply ignore them?

  2. Thanks for this very informative article and for all your hard work.

    You write

    ‘But of further concern, these effects were seen even if the drugs had been stopped years before the onset of dementia.’

    Do you have any more information about this such as whether length of time or dosage strength related to these effects?

    Severe cognitive difficulties seem to be part of the picture for some people with psychosis right from the beginning. I am thinking the effects you are talking about are ones that are more gradual over time?

    Do you have any suggestions for further reading about pscychosis and cognitive difficulties?

  3. This reminds me of a woman who had a shield alert out some years ago after suffering a bad reaction to steroids given to her after surgery and winding up in the ER and being forcibly admitted to the psych unit. She wound up involuntarily comitted to a state mental hospital for many months if I recall, and the more they drugged her, the more signs of “dementia” she showed, and then they used that to make her a ward of the state and the forced drugging became permanent without even a need for court order. Someone here may know more about this tragic case than I do, but I only bring it up with vague recollection because it’s relevant to the reality behind the topic in this article. I’m sure it happens to many thousands of people a year. Added to the brain damage caused by neuroleptic drugs, and I’m sure this is happening to a million or more.

  4. I have been taking some form of psychiatric drug for going on 26 years. I was institutionalized during two periods (1989) and (1990). I have either been a full time student or gainfully employed for the last 24 years. I realize that Soteria is designed for people with a first case episode, but given my fairly good track record and the accumulating evidence of the harm of these drugs, is there not some place to go to safely detox, even if it takes me six to nine months? I currently take 2.5mg of Zyprexa, and .5 mg of klonopin. I think that insurance should cover this, given the tens of thousands of dollars already down the rat hole for hospitalization, drugs, lab tests, psychiatry visits, monitoring for the abuse done by Lithium to my kidneys, not to mention the future medical dilemmas I face. I am 54, and I have a son who is a merit semi finalist. I think that I must be doing some things right, and deserve the opportunity to finally divorce myself from psychiatry, and still be able to eke out some of life’s pleasures in old age.

  5. I’m so not surprised. I’ve tried Zyprexa and the side effects I had, although I took a very small dose (cutting the smallest pills into 4) were horrific and the withdrawal reaction continued for at least a week after a single dose. These things are so toxic it’s incomprehensible to me why they are used in the first place (well, maybe the reason is: money).

  6. I dealt with a whole bunch of anticholinergic intoxication poisoning, according to drugs.com.

    Initially, I had anticholinergic intoxication poisoning caused by Voltaren 50mg, Ultram 50mg, Risperdal .5 mg – 2 mg, Lithium, 900mg – 1200mg, Seroquel 50mg – 400 mg, and Zantac 150 mg – 300 mg. This lasted for about four months.

    I had anticholinergic intoxication poisoning caused by Voltaren 50mg, Ultram 50mg, Lithium, 900mg – 1050mg, Seroquel 50mg – 400 mg, and Zyprexa 10mg – 20 mg. This lasted for approximately four months.

    Then my psychiatrist created anticholinergic intoxication with Voltaren 50mg, Ultram 50mg, Lithium, 900mg, Zyprexa 10mg – 20 mg, Proxyl 200mg, Geodon 240 mg, and Tregretol 150 mg. This lasted for approximately four more months.

    Then my psychiatrist created anticholinergic intoxication poisoning with Voltaren 50mg, Ultram 50mg, Lithium, 300mg – 900mg, Geodon 20 mg – 240 mg, Wellbutrin 150mg – 300 mg, Topomax 25 mg, and Carbitrol 200 mg – 500 mg. This lasted approximately 21 months, although much of this was a prolonged weaning off all these major drug interaction laden drug cocktails.

    “We need to use these drugs with caution. Dose matters. Length of time a person is on them matters. Polypharmacy matters.” Think I’ll end up with dementia, Sandy? No family history of it.

    And lets hope the psychiatrists some day learn that creating anticholinergic intoxication in patients with massive drug interactions is not actually “appropriate medical care,” and it’s not “bipolar” either. It’s anticholinergic intoxication poisoning. My “bipolar” etiology was the common adverse withdrawal effects of Wellbutrin, given for smoking cessation, worsened by the Voltaren and Ultram adverse effects.

    Isn’t it great we can medically explain the etiology and causes of “bipolar” now, however?

    • No answer for those of us who dealt with medically provable iatrogenesis, Sandy? I mean no disrespect, but this may be why some here doubt your motive when claiming it is appropriate to maintain the psychiatric industry’s right force medicate people. My pastor has already confessed that psychiatric stigmatization, tranquilization, and poisoning with major drug interactions is the historic “dirty little secret of the two original educated professions” way of covering up easily recognized iatrogenesis and clergy sins.

  7. “I have come back to this theme again and again. This is not an anti-drug discussion. It is a respect-the-drug discussion. We need to use these drugs with caution.”

    … say the people who have never been subjected to the suffering of psychiatry and the horrors of psychotropic drugs. Respect people. Reject drugs.

    “Dose matters. Length of time a person is on them matters. Polypharmacy matters.”

    People matter. Lives matter. Slay the Dragon of Psychiatry.

  8. Wow, great discussion. It amazes me how complex the brain is, and the multiple, varied effects of drugs on our brains. As an E.R. Nurse, I have also learned about the tremendous lack of knowledge that Physicians have for the side effects (and direct effects) of medications. They usually do not have the time, or interest to keep up. I fairly recently learned about the fact that histamines are also neurotransmitters in the brain. In a very informal survey, I mentioned this to some Physicians and it seems that about 1 in 3 are aware of this fact, but I have not asked that many. Almost zero nurses are aware of it. The public is entirely unaware of it in my experience. The topic comes up a lot, because people often mention that “antihistamines make me feel weird”. I personally use them sometimes for allergies and they make me feel weird too- I break the allegra in thirds and take is as needed. I have even noticed some decrease in inhibitions, and increased lack of self-control (although I know I am still ultimately responsible for that). I remember reading someone who suggested that antihistamines could have been marketed as anti-depressants because of their similarities had they come out at an opportune time, or had been marketed for such use. (I wonder how many violent outbursts/ suicides might be linked to antihistamines?) This is fascinating and alarming about their link to dementia. I have seen benadryl break the severe EPS reactions of neuroleptic use even prior to the administration of cogentin ( and even rarely be the only drug used for this). I assume this is because of their anticholinergic properties, although I am not certain if this is the primary drug action that breaks the dramatic tonic EPS reactions (Does anyone know this off hand?). This has big implications for the millions taking antihistamines daily for allergies along with their use for psychiatric problems. I love your thoughtful posts!!!