Benzodiazepine Use and Risk of Alzheimer’s Disease

Philip Hickey, PhD
20
285

On September 9, 2014, the British Medical Journal published an article by Sophie Billioti de Gage et al.  The article is titled Benzodiazepine use and risk of Alzheimer’s disease: case-control study.  The research was a study based on data from the Quebec health insurance program database.

Here are the authors’ conclusion:

“Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.”

Here’s how the study was conducted:

Individuals were selected as “cases” for the study if they met the following criteria:

1.  “A first diagnosis (index date) of Alzheimer’s disease…recorded during the study period without any record of another type of dementia at the index date or before”
2.  “Absence of any anti-dementia treatment before index”
3.  “At least six years of follow-up before the index date”

Each person with Alzheimer’s was matched on gender, age group, and duration of follow-up (6, 7, 8, 9, or 10 years) at the index date with four controls.  Both cases and controls were randomly selected from people over age 66 living in the community in 2000-2009.

Data on benzodiazepine use was collected for each case and four controls for the period 5-10 years before the index date.  The following data was collected:

1.  Any use of a benzodiazepine during the stated time frame
2.  Cumulative dose
3.  Whether the benzodiazepine used was long (> 20 hours) or short (< 20 hours) elimination half-life.

The specific benzodiazepines identified in the study were:

Long-acting:  bromazepam; chlordiazepoxide; clobazam; diazepam; flurazepam; nitrazepam; clonazepam.

Short acting:  alprazolam; lorazepam; oxazepam; midazolam; temazepam; triazolam.

Here are the results:

Billioti Table 3 highlighted

In summary:  Use of benzos was significantly associated with an increased risk of Alzheimer’s Disease (AZD). The odds ratios are:  1.52 for any use; 1.85 for long-term use (6 months or more); and 1.72 for use of benzos with a long half-life.  The corresponding odds ratios, after adjustment for potential confounders including anxiety, depression, and insomnia, were 1.43, 1.74, and 1.59 respectively.  The 95% confidence limits for each of these ratios are shown in the table.

Here are some quotes from the discussion section of the paper:

“Risk increased with density of exposure and when long acting benzodiazepines were used. Further adjustment on symptoms thought to be potential prodromes for dementia—such as depression, anxiety, or sleep disorders—did not meaningfully alter the results.”

“Our findings are congruent with those of five previous studies…”

Limitations:  This was a case-control study; not a randomized, controlled trial.  Therefore it is not possible to say with absolute certainty that the benzodiazepine use caused the excess incidence of AZD.  It could be argued, for instance, that the benzos were being prescribed to treat early (prodromal) signs of AZD.  This would be an instance of what’s called reverse causation bias.  However, the authors took particular pains to inoculate the study from this bias:

1.  They did not count as “cases” people who received benzos in the five years prior to the AZD diagnosis date. So if the finding is an instance of reverse causation, it has to be acknowledged that the AZD had an extremely slow and, incidentally, unrecognized onset.

2.  They measured cumulative dose and found a direct association between the magnitude of the dose and the risk of contracting AZD.

3.  They noted whether the benzos used were long or short acting and found the association stronger in the former. This is essentially another cumulative dose measure.  A person taking a 20-hour benzo daily is always effectively “dosed”, whereas a person taking a 2 hour compound daily will have significant breaks from the drug every day.

4.  They calculated the odds ratios after adjusting for the presence of anxiety, depression, and insomnia. These are the kinds of problems for which benzos are often prescribed, and could conceivably also indicate the early stages of AZD.  The fact that the association was still strong after adjusting for these factors makes the possibility of reverse causation bias even less likely.

Some more quotes from the study:

“Dementia is currently the main cause of dependency in older people and a major public health concern affecting about 36 million people worldwide.  Because of population growth and demographic ageing, this number is expected to double every 20 years and to reach 115 million in 2050.”

“Prevalence of use [of benzodiazepines] among elderly patients is consistently high in developed countries and ranges from 7% to 43%.”

“Although the long term effectiveness of benzodiazepines remains unproved for insomnia…and questionable for anxiety…their use is predominantly chronic in older people.”

“Our study reinforces the suspicion of an increased risk of Alzheimer type dementia among benzodiazepine users, particularly long term users, and provides arguments for carefully evaluating the indications for use of this drug class.  Our findings are of major importance for public health, especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries.” [Emphasis added]

Psychiatry’s Reaction to the Study

In general there has been little reaction from psychiatry to the study.  I was unable to find any comment from the APA or from the Royal College of Psychiatrists.  I have found a small number of comments from individual psychiatrists.

Guy Goodwin, MD, is a professor of psychiatry at Oxford University in the UK.  He is also president of the European College of Neuropsychopharmacology.  In a BBC article dated September 9, he is quoted as saying that the findings:

“…could mean that the drugs cause the disease, but is more likely to mean that the drugs are being given to people who are already ill.” [Emphasis added]

There’s no indication in the BBC article that Dr. Goodwin cited any evidence for this assertion, or that he made any reference to the steps that the authors took to counteract precisely this kind of reverse causation bias.

. . . . .

I also found a comment from Abbot Granoff, MD, a psychiatrist practicing in Norfolk, Virginia.  His comment was in response to a CBS article.  Here are some quotes from his comment.

“I am a Board Certified Psychiatrist…”

“I have been successfully prescribing benzodiazepines for the past 35 plus years in my private practice.”

“…anxiety, depression or insomnia might be early symptoms of dementia whatever the cause. Prescribing a benzodiazepine to treat these symptoms does not cause the illness.”

“Because of age, liver function (which breaks down medications) or brain function might already be compromised and cause the side effects of sedation and memory loss to become more severe. These side effects are dose related. Reducing the dose eliminates the side effects. They are not permanent.”

Again, there is no evidence, and no serious acknowledgement of, the issues – just the comforting (?) assertion that “prescribing a benzodiazepine to treat these symptoms does not cause the illness.”

. . . . . . . . . . . . . . . .

By way of contrast, I found an interesting comment in the BMJ’s rapid response section.  The comment is from Eric Lenze, MD, geriatric psychiatrist, et al, of Washington University School of Medicine, St. Louis, Missouri.  Here are some quotes:

“A mass of evidence suggests that the benefits of benzodiazepines in older adults rarely, if ever outweigh their risks.”

“Benzodiazepine risks, whether short-term or chronic, include cognitive impairment, delirium, respiratory insufficiency, falls, fall-related injuries such as hip fractures, motor vehicle crashes, and death.”

The main risk factor for chronic benzodiazepine use is any previous use, so an intended short-duration prescription of these habit-forming medication is likely to lead to their long-term use.” [Emphasis added]

“Benzodiazepines’ benefits for anxiety disorders are questionable, especially as they are commonly used in clinical practice. First, the dose of benzodiazepines necessary to provide a clinical response is far higher than that needed to cause harms in older adults – for example, 6-10mg daily of alprazolam is needed to bring about remission from panic disorder, and 30-60mg daily of oxazepam was needed for response in (to our knowledge) the only controlled study of benzodiazepines for anxiety disorder in older adults.  Second, there is growing evidence in anxiety disorders that benzodiazepine use reduces the efficacy of exposure-based cognitive behavior therapy, probably by interfering with learning and memory and preventing habituation to the anxiety.  Hence, benzodiazepine use may actually perpetuate (rather than treat) many anxiety disorders by preventing naturalistic recovery from them.”

“The evidence for benefits of benzodiazepines in insomnia is equally poor. In a meta-analysis, benzodiazepine use resulted in a mean nightly improvement of 25.2 minutes sleep. The number needed to treat for improvement of insomnia was 13, while the number needed to harm was 6.”

“For occasional insomnia or transient anxiety, watchful waiting or other low-intensity intervention are superior to initiating a dangerous and habit-forming medication.”

“To conclude, Billioti De Gage and colleagues provide more evidence still that deleterious consequences of benzodiazepines in older adults are a large and growing public health problem, given their high rates of use in this age group.  It is time for their use to be limited, for example to palliative and hospice care or specific treatment-refractory cases, and as a start we recommend the following:

1.  Clinicians prescribing these medications to older adults should warn them that their use is not considered best practice.

2.  These medications should come with a warning (like that found on cigarette packages) such as “If you are older than 60, use of this medication will increase your risk of cognitive impairment, falls, hip fractures, and death.”

3.  Educate health care providers regarding (a) risks of short-term and long-term benzodiazepine use and (b) safe alternatives for the management of anxiety and insomnia.”

“Competing interests: none to report”

There are 20 references attached to this comment, so it’s a good source document for anyone wanting to research the facts about these dangerous drugs.

A Consumer’s Reaction to the Study

Here’s another comment from the BMJ’s rapid response thread:

“I have been prescribed generic Xanax for about 9 years, at dosage between 5mg and 1mg/day. I am 45.  This study is clearly alarming, and honestly terrifying.

How are my odds of being diagnosed with Alzheimer’s figured?  I can only imagine that I am in increased likelihood of about 8,000%.  Based on the 3-6 month likelihood rates.

My doctor says, ‘Just keep taking it. Benefits outweigh the risks.’ Clearly, they do not! I have not slept nor eaten well since I read the study.  Can anyone explain the likelihood ratios that are mentioned?  And is there evidence of the disease showing up in younger people after taking benzos for years?

Any help, and perspective at all would be so very much appreciated!”

Discussion

So, if a person in mid-life is feeling anxious, or depressed, or can’t sleep?  No problem.  No need to figure out the source of these concerns.  No need to work towards solutions in the old time-honored way of our ancestors.  Today, psychiatrists have pills.  Pop a benzo!  And by the way, you’ll have a 40% increased risk of AZD in your late sixties.  And if that makes you anxious, don’t worry; psychiatrists have neuroleptics and electric shock “treatment” to “manage” dementia.

All psychiatric drugs exert their effect by distorting normal brain function.  They all cause damage, especially when ingested for prolonged periods. The present study simply confirms and quantifies this phenomenon.  Psychiatry’s usual response to this is to assert that the benefits of their “treatments” outweigh the risks.  But by  what Faustian calculus can one compare the short-term chemical dissipation of anxiety with the medium-term risk of AZD?

There is truly no human problem that psychiatry can’t make ten times worse.  The notion that all the great trials of life, and particularly aging, can be resolved by dispensing addictive drugs is fundamentally spurious, disempowering, and insulting.  The notion that such activity would masquerade as a legitimate medical specialty is a travesty, to which our descendents will one day hold psychiatry accountable.

Anxiety and depression are not illnesses.  They are normal human responses to various kinds of problems that are an integral part of what it means to be human.  The only effective way to cope with anxiety or depression is to confront, and resolve, the underlying causes, either by one’s own efforts, or with the help of others.  Taking psychiatric drugs to “treat” these feelings is no different than “drowning one’s sorrows” in a bottle of whiskey.  Both products are highly addictive, and the long-term results are comparable.

Detoxing From Benzos

Detoxing from benzos, even after relatively short-term use, can be extremely difficult and fraught with problems.  These drugs should never be stopped abruptly.  For information on withdrawal from benzos, see Monica Cassani’s site Beyond Meds.

* * * * *

 

This article is cross-posted on Philip Hickey’s website,
Behaviorism and Mental Health

Support MIA

Enjoyed what you just read? Consider a donation to help us continue to produce content, provide up-to-date research news, offer continuing education courses, and continue building a community for exploring alternatives to the current paradigm of mental health. All donations are tax deductible.

$
Select Payment Method
Loading...
Personal Info

Credit Card Info
This is a secure SSL encrypted payment.

Donation Total: $20.00

20 COMMENTS

  1. Dear Philip
    Thanks for the great (and frightening) article. Its possible to do something about anxiety through heading in the right direction, by changing what’s inside, its harder at the start but it gets a lot easier with practice.
    Whatever substance a person takes is likely to make things worse and this is a fact that we’ve known for centuries.

  2. I am so glad that I threw away the bag of drugs that I was given when discharged from the psych hospital. It was a nice, hefty brown paper bag. Contained therein was a so-called “antidepressant” and two sleep aids, both of which were benzos. My wonderful psychiatrist who gave them to me never once told me the effects of the “antidepressant” or the benzos. The “antidepressant” can causes heart attacks and we all know what the damned benzos can do. I took the bag and threw it in the dumpster and never looked back. I’d been on those damned things for the two and a half months I was in the psych “hospital.” Later on I had a heart attack! Go figure! I’m still waiting to see if I’ll suffer any effects from the benzos.

    • I remember thinking at the discharge, when the “good professional” aka torturer was giving me a list of drugs (like 3 of them including a benzo) and “good advice” on how to take them, that I was not intending to take that shit ever again. These idiots (and I am being generous here by not implying ill will) drugged me up to my nostrils for 5 days straight with high doses of psych drugs including benzos, triggered an almost compete anterograde amnesia and I was still allegedly throwing chairs at them (which they rightly deserved) – so much about benzos doing anything to help against anxiety, agitation or whatever they’re supposed to help against. When I later complained about the rape and torture I endured in this hellhole they had the audacity to write they treated me according to best practice and that I was offered psychological counseling and a wide range of activities. I can’t speak to the truth of these things since I don’t remember shit but I doubt even if that was true and I didn’t laugh in their faces at the idea that it’d be of much help given I can’t remember anything. 5 days observation for 24h and they missed complete amnesia. That’s professional indeed.

  3. Hi Stephen,

    In all fairness, none of the sleep doctors tell you the side effects of the meds they prescribe. And really, since I can easily access the information on the net, since time is so limited, I would rather focus on other issues. As long as they don’t blow me off if I complain about a side effect which hasn’t happened since none of them work which is probably a good thing.

    I am curious, why did you need two sleep aids? Of course, I am asking that in a facetious manner.

    • Well, now that you ask I will tell you why I ended up with not one but two benzos for sleep.

      I am a very light sleeper as it is and I had lived alone for most of my life up to the time of being in the “hospital.” So, here I am in a “hospital” where I had to share the room with a roommate, where the nurses laughed and yelled all night long at the nurses’ station, and where the rules state that someone must check what you are doing at night every half hour. A nurse and a behavioral health worker go into each and every room and shine a light in your face to see if you’re asleep or not! The more humane actually shine the flashlight on the side of your bed and can tell whether you’re asleep or not from the reflection of the light. But most of the nurses, and it’s always the nurses that have the flashlight, actually shine the light in your face! I actually told this one nurse who was notorious for doing this that if she did it again I was going to get up and moon her. She promptly went down to the charge nurse and told her that I threatened to get up and knock the you know what out of her. She then wrote it into my chart, making it an official threat that was lodged in my records permanently. Even though my roommate went down and told the charge nurse that the other nurse was lying everyone refused to remove the notation from the chart. After all, the nurse was more important than any of us and everyone knows that you can’t trust the word of a “mental patient.”

      The nurses on the evening/night shift always made noise the entire shift. They laughed and yelled up and down the halls to one another and to the other staff. On some nights I went down to complain to them about their loudness three times, to no effect. Consequently, I lodged a formal complaint which by law had to be investigated, and the charge nurse for that shift got reprimanded. She was so angry that she assembled the entire unit in the dining room before she left for the day and carried on about how ungrateful a certain “someone” was to have lodged a complaint against her and her nurses. I raided my hand and stated that she was obviously talking about me and I told her that if the noise at night didn’t stop that I’d write another complaint!

      And so, this is how I ended up with not one but two sleep “aids.” They were determined to drug me to sleep one way or the other because they didn’t like me calling them to account for their terrible behavior. One night when I went down to complain about how loud the nurses were I told them, “I know that we’re only “mental patients” and that we really don’t count for anything as human beings as far as you all are concerned, but we need to have our sleep too.”

      • Hi Stephen–

        This is the kind of story, a disillusioned first-timer’s revelation of the stinking attitude problems on which the whole field is based, that shows how easily and quickly anyone could get to the point of the injustice of forced treatment who wanted to. I can’t believe how many people expect to get trusted and do win the loyalty of their readers who downplay and leave aside the insipidity and malignant intentions of people who use the system to play God and boss around the un-people. It’s a constant.

      • In a hospital I was imprisoned in there was a completely normal teenage guy who ended up there for marihuana charge (preferred a few weeks in a”hospital” to jail and criminal record). He was put in one room with some 6 guys and couldn’t sleep – they put him on such heavy duty pills that he complained to me about it (“this is something heroin addicts would take”). Psychiatry 101 – the author is right by saying there’s no problem that psychiatry can’t make 10 times worse (10 times being an underestimation). And these morons/criminals are allowed to force you to take these poisons and keep you imprisons and torture and violate you.

  4. Wow Stephen, I wish I could say in this post what I really thought of those nurses but I don’t want this comment to be deleted. I just thank my lucky stars every day that I never saw the inside of a psych hospital. The thought of that makes me shake as I write this post.

    • You’re lucky indeed. By my own experience: all the “danger to self and others” is a direct result of how they treat “patients”. They have abused me so badly that I first tried to kill myself and then allegedly threw chairs at them (I can’t remember it though – I was so drugged up on benzos). I actually find it incredible that so few psychiatrists are getting harmed or killed in these places but to be honest I have no sympathy for them. Every “patient” who does that is merely defending him/herself. I can’t stand the whiny attitude “oh, it’s so hard to work in a psych ward, patients are so aggressive”. I believe that’s called projection.

  5. The evidence base for Benzos is only in the 6-8 week range, and the product information itself says that it is not intended for long-term use. The best analog to benzos in terms of effects on the brain and body is alcohol. Taking a shot definitely does help you sleep in the short term, but anyone using a significant dose of alcohol to sleep every night is going to be in for trouble in the long run. It is noteworthy that long-term alcohol abuse does lead to a form of dementia in many people. Why any doctor would prescribe benzos long-term is baffling, and in my mind, it is criminal behavior.

    —– Steve

    • “anyone using a significant dose of alcohol to sleep every night is going to be in for trouble in the long run”
      …and even that is ignoring a portion of the population who don’t get sleepy on alcohol (I am one of these people – even small amounts give me sleeplessness and I don’t fall asleep unless I either sober up or drink so much that I pass out). It’s the same for benzos – there are people (myself again included) who don’t get calmer – they get more upset, anxious, aggressive and what not (it’s called “paradoxical reaction”). But of course that is being denied by the “good professionals”.

  6. Dr. Hickey,
    Thank you for yet another incredible article. Your scholarship and attention to detail takes my breath away. May I speak for so many of us under the the thumb of this system and say:

    We are so lucky to have you on our side.
    Your integrity is very moving, and does not go unnoticed for one moment.

    I wish there was some medal we could hang around your neck.

    Thank you so much for your tireless advocacy.

  7. Well, I will add my voice to all the other praise. Dr. Hickey, your article are so well-argued and relevant, and I always look forward to reading them.

    Do you think the indiscriminate prescribing of benzos and drug company payments to doctors are connected? I know this was a kind of stupid question. I think I should have said, did the new federal database about payments to doctors reveal anything?

    • Ted,

      There’s some interesting history. In the 60’s, the other professions were starting to encroach on psychiatry’s turf. At about the same time, psychoactive drugs began to be discovered. The drug companies needed licensed medics to prescribe the products, and the psychiatrists needed something to distinguish themselves as different from psychosocial practitioners. So the marriage took place. The spurious and destructive practices of psychiatry, coupled with the virtually unlimited financial backing of pharma, has produced what is arguably the most destructive development in human history.

      The financial disclosures may help some, but my guess is that the participants will find ways around it.

      Best wishes.

      • Dr. Hickey,
        I am a woman who went through a blistering taper from Klonopin from November 2012 – November 2014. I was given the drug for nerve damage in my face that resulted in a horrific chronic pain condition. I took the drug for 23 years. I never knew about the dangers of the drug. I never knew that it was a benzodiazipine. I never knew what a benzodiazipine was until I decided to stop taking the drug. The fallout from the taper and withdrawal is so widespread. I understand that the recovery comes over a period of time after the last dose has been taken. I feel like a shadow of my former self. There was no question that I would see this through after I realized what this drug was. I would like to put my experience to good use by helping spread the awareness of the dangers of these drugs. It is almost impossible to describe the nightmare of benzo withdrawal. Would you have any suggestions (not to include internet support groups) as to how I can help others? I understand that you live in Colorado. I am also a resident. I was working with Boulder Community Health to start a mentoring program to help patients withdraw from these drugs. I was told that the proposed plan was stopped due to a lack of funding. In my eyes it is clear that garnering the strength to see the taper though is a monumental task. Do you have any input as to how I may help?