Benzodiazepines and Dementia

[checktest]

Pretty sure most have seen articles correlating dementia and benzodiazepine use, e.g.

Benzodiazepine use and risk of dementia: prospective population based study

Objective To evaluate the association between use of benzodiazepines and incident dementia. Design Prospective, population based study. Setting PAQUID study, France. Participants 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until...

www.bmj.com

Association between Benzodiazepine Use and Dementia: A Meta-Analysis

The association between long-term benzodiazepine use and risk of dementia remains controversial. Therefore, current study aimed to quantify this association, and to explore a potential dose–response pattern.We searched PubMed, Embase and the Cochrane ...

www.ncbi.nlm.nih.gov

Questions remain of how much is related to the drug vs. indications for taking it (anxiety and insomnia / dementia risks, epilepsy and long-term BZD use, other neuropsychiatric conditions, elements of Alzheimer's, etc...). Cognitive effects and testing vs neurodegeneration. Size of potential actual effect, and so on.

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Just curious on thoughts here around the topic, as well as mechanisms related to a possible connection.

Part of this was spurred by this article

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are...

www.frontiersin.org

Especially the Midazolam Tau hyperphosphorylation mouse study from 2019.

Administration of the benzodiazepine midazolam increases tau phosphorylation in the mouse brain

Preclinical studies have shown that anesthesia might accelerate the clinical progression of Alzheimer's disease (AD) and can have an impact on tau pat…

www.sciencedirect.com

(Which, while finding tau hyperphosphorylation with midazolam notably didn't find major aggregatory changes, though degenerative effects were there. The H(P) persisted past some drug time.)

Hyperphosphorylation of tau (depending on where in tau and the settings) is prevalent in the tauopathies and connected to Alzheimer's, historically as neurofibrillary tangles, with a whole tau hypothesis. Amyloid-beta - tau interactions ("AB as the gun, tau as the bullet").

[Decent open paper showing some of the historical hypotheses for Alzheimer's.

History and progress of hypotheses and clinical trials for Alzheimer’s disease - Signal Transduction and Targeted Therapy

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss along with neuropsychiatric symptoms and a decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, and neurofibrillary tangles in the brains of...

www.nature.com

]


Neurotrophic effects of benzodiazepines.
Could BZDs interfere with adaptive BDNF responses in some situations? https://pubmed.ncbi.nlm.nih.gov/223...eurotrophic-factor-level-under-mental-stress/

A Benzodiazepine Impairs the Neurogenic and Behavioural Effects of Fluoxetine in a Rodent Model of Chronic Stress - PubMed

Antidepressant agents such as fluoxetine have been shown to produce neurogenic effects involving transcriptional and translational changes that direct molecular and cellular plasticity. These cellular and molecular events appear necessary to mediate the therapeutic effects of fluoxetine and may...

pubmed.ncbi.nlm.nih.gov

Is it an acute vs. chronic effect?

Alterations in Brain-Derived Neurotrophic Factor in the Mouse Hippocampus Following Acute but Not Repeated Benzodiazepine Treatment

Benzodiazepines (BZs) are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the...

journals.plos.org

NGF - could there be a cell-type specific interaction or problem with some neurites?

Peripheral-type Benzodiazepines Influence Ornithine Decarboxylase Levels and Neurite Outgrowth in PC12 Cells - PubMed

A number of the benzodiazepines (BZDs) inhibit nerve growth factor (NGF)-induced neurite outgrowth in a dose-dependent manner in PC12 cell cultures. The rank order of potency of a series of BZDs for inhibition of neurite outgrowth does not correlate with the order of their affinity constants for...

pubmed.ncbi.nlm.nih.gov

Not sure about GDNF.

I don't see some excitotoxicity being exacerbated by benzodiazepines, but perhaps homeostasis is thrown off from some circuits being disinhibited or in tolerance to benzodiazepine effects / GABAR distribution.

Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission

Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer’s disea…

www.sciencedirect.com

Or perhaps only minor interactions and noise.

Could benzodiazepines exacerbate the course of the dementia, independently of posing as a possible risk factor? Is every old person going to get melatonin drugs and low dose trazodone (or seroquel) instead?

I mean, I don't think benzos are quite like anticholinergics, and there are a lot of issues going on, but sometimes the associations give you a bit of pause. Not a primary risk factor but something to evaluate.


What are your thoughts on benzos and dementia?

 

[Lil'LinaptkSix]

Do not know if this is relevant to this thread but if I take 1mg alprazolam the next day there will be a memory "loss" of a couple hours following the ingestion of the alp.
If I ingest 4mg alp a day for a week at work I will remember very little of the work week but just breezed through it all.
I'm like, "Who got all this cleaning done?"... "You did it Wednesday, remember?"... "Nope."

 

[checktest]

Yeah, do the cognitive effects (memory loss and whatever) have more insidious long-term consequences or is that more of an acute aspect.

 

[AlphaMethylPhenyl]

Did you do any analysis of those studies beyond the title??

Reports vary a lot. If someone is way anxious, that will probably kill more brain cells than being on a benzo. If someone abuses their benzo, they're at much more risk for toxicity. Experiences vary...

Everyone's all "neurogensis neurogeniss neurogenisis". Well, that's how brain tumors can be formed. That said, the dendate gyrus and neurotrophic activity tend to be healthy mix.

Experiences vary. Some say there has been a coverup on their effects. I think that if it were anything truly critical, that we would have found out. Benzos have been in widespread use since the 1960's.

It used to be the thing to stay drunk all day, or at least always have a few drinks in you. And while booze produces a scatter-shot of activity, it's mainly a GABAergic.

Fast-forward: basically selective GABAergic depressants overall have been used since the 1800's--bromides then barbs. Bromides aren't anymore because they have been found toxic. Chloral hydrate thought was a 19th century thing, and GABAergic--not health food, to say the least, but not mass cases of dementia. But barbs were used widespread pretty early. Let's do some research...ear;ier than I thought. I'd say by 1910 they were probably mass produced. It's true that our science in measurement was way primitive back in the 19th century, if extant. But mid-19th century studies are more rigorous than the rep they get for it. So given that rigorous studies have been conducted on them in the last several decades

Surprising nonetheless because I have seen studies that conclude some deficit in cognition in some domains, but I think this is the most recent one. It would be wise to check for conflict of interest (I haven't the time). From late 2019:
Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis.

 

[sekio]

. Bromides aren't anymore because they have been found toxic

The incredibly long half life also makes them poor drugs.

As for BZDs and dementia/the elderly, my grandmother (rest her soul) was diagnosed with Parkinsons disease in her later years and (between the natural progression of the disease and the medication used to "treat" it) she was an absolute wreck who, on a good day, was cowering in fear and confusion at her own daughter. Start her on the usual Parkinsons meds, and she would present some symptom like agitation, which the doctors would "treat" with lorazepam prn, then an antidepressant to elevate her mood, lithium because why not, maybe we should add ECT to the mix? And so sooner or later you have an 80-year old whose remaining brain cells are caught in the crossfire between the two dozen different medications all pulling in seperate directions.

Benzos have no place in geriatric medicine aside from occasional acute usage. Grandma does not need to be pumped full of Klonopin and jammed, slack-jawed and drooling in a broom closet. I've heard stories of whole retirement homes being transformed overnight from zombieland to a bunch of active people doing things simply by reducing the amount of BZDs handed out like candy.

 

[checktest]

Spoiler: To ??

[Yeah, I really do need to improve the quality/organization/logic of my posts/writing with some analytical content from my documents, so I don’t come off as an ignorant guy posting random Pubmed searches and tenuous links without direction. (I mean, not that I actually am not that…or not scattered, or actually know anything, haha. I tend to be overly general and superficial, and can work to improve and express more cogently. Well, hopefully.) I did read beyond titles but didn’t write out enough. I mean I feel annoying how I post some things, especially in this subforum with some people active in relevant fields. Not wanting to be a scattered stimmer or something. I just tend to get paralyzed/repetitive when writing/expressing, and come from not writing much at all. Trying to post something rather than nothing at all. As for papers, still transitioning to Zotero from Mendeley and others, annoying word/online plugins. And stop posting so much from my phone so I can write out more. Well, probably edit more easily and take out. Sorry about that.]

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Agree about the neurogenesis. You’ll see people take something like dihexa and other experimental drugs without any consideration of long-term consequences. I had a family member die of a GBM and it really is nasty. Still when you see research like (Moreno-Jiménez et al., 2019), it makes you wonder about selective regional enhancements and mechanisms to combat some degeneration, as well as risks.

In terms of anxiety, of course it and conditions like it cause damage on their own. I didn’t mean to come off as denying valid uses or minimizing the damage of such conditions/diseases. Psychiatric conditions are damaging. (I know well myself with some of the neurostructural studies of longer-term depression such as hippocampal loss / atrophy correlated with duration of depression, I have a slightly off MRI myself). The question is where does the balance lie for use of some treatments in the face of other alternatives or personal risk factors like apoe4? Risk-benefit. Relevant to this forum, how much would abuse and dependence contribute?

There are also questions of whether more observations of dementia connections are present now because other causes that would have previously caused death have been managed more effectively. i.e. the alcoholics now living through some heart disease and cirrhosis present with the dementia. Can’t get diagnosed at 83 with AD if you died from an MI at 51, and so on. As our ability to treat some diseases improves, other delayed risks evolve. I mean some dementia is decreasing, often from other treatments and environments (say vascular dementia and actual control). But the baseline life expectancy has changed, so what will be the quality? Widespread use of barbiturates occurred in time periods where life expectancy and some risk control were different, in addition to what you mentioned in measurement and science of the time.

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I'll try to write out more of what I was thinking at the time.

The available meta-analysis (trash PLOS but used because it was available for the post) and example prospective study from Billioti de Gage did have some notable issues. The 2012 de Gage study based on 1000 French people didn’t have control for some anxiety and insomnia factors, though a later 2014 did. The nested-case control aspect that put an odds ratio of 1.55 has room for selection errors - a 50% greater chance of dementia with some populations. The meta-analysis claims a ~20% (per 20 daily dose per year), without fully acknowledging the lack of some dose response in some studies, basing it only on a few studies. Missing data for benzodiazepine use in some areas may be inadequately controlled.

A comparative UK cohort study that defined use and some measures slightly differently found no connection for BZDs and AD in any use (while finding an association with anticholinergics), though recurrent use at 1.30 IRR for BZD and measurement definitions are worth reviewing. (Grossi et al., 2019) Differentiating between AD and other dementias (and not just by some EMR or claim codes but some pathology or amyloid scan would be preferable) seems to be an issue, as well as mild cognitive impairment grouping. Ever/Recent/Chronic. The largest study, from Finland(Tapiainen et al., 2018) , found a mild difference, dose-dependent, but not different across time of action. Interestingly, interference with some other medications was put forward in terms of defining effects on the severity of the dementia. BZDs affecting some ADs(as below), cholinesterase inhibitors or memantine perhaps.

Dose-dependence and especially type of benzo are interesting considerations – I wonder how the relative country use of some drugs and prescription patterns, as well as population vulnerabilities, contribute.

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As for the BDNF section and the papers, I don’t know much with the full effects of benzodiazepines on BDNF in some areas, and how that applies.

The initial review mentioned (Zhao et al., 2012), where low and medium doses of diazepam (in mice) benefited short term in chronic stress, showing positive effects in hippocampal neuroplasticity and glucocorticoid responses. This changed to decreased BDNF (and synaptophysin) on low term (4wk+) administration of diazepam. High doses were problematic.

(The mouse) study (Licata et al., 2013) used a large dose of diazepam relative to the Zhao, with minimal BDNF effects in hippocampal tissue over a 7 day period. However, triazolam and zolpidem affected BDNF levels in the hippocampus. (It proceeded to review zopidem effects with a mechanism of BDNF reduction due to a MeCP2 increase decreasing BDNF transcription at a particular promotor and some CREB connection.) I was curious whether a longer diazepam period would have differential effects, or whether it was counter to Zhao, as well as the relative injection protocol. Is it acute(say with high doses) or chronic? Drug differences.

A different, small paper(Tamaji et al., 2012) (in humans) showed no beneficial effect on serum BDNF with (a quite small 5mg) of diazepam, relative to a positive response with paroxetine in a stress task. Too small and weak but conceptually interesting in terms of environmental factors and drugs.

If BZDs weren’t directly problematic in terms of BDNF, could they decrease the effects of other drugs that might be beneficial in certain conditions? (The mouse) study (Sun et al., 2013) used an isolation model, studying hippocampal markers. A fairly large dose of diazepam (less then Licata) prevented beneficial effects of fluoxetine (restoration of new hippocampal neurons). Is it the dose, a drug effect, just some random measurement? How would altered neurogenesis over a greater time affect humans?


As for NGF, the old (cell culture) paper (Morgan et al., 1985) showed an interesting differential of inhibiting neurites, with diazepam at a (+++) potency vs. clonazepam (-). I remain curious about the relevance of different benzodiazepines to possible neurodegenerative effects in different types of use. The ‘We suggest the possibility that BZDs may have a cytoskeleton-destabilizing activity, which could account for the inhibition of neurite outgrowth.’ In line with this supposition is the finding that diazepam can selectively inhibit the synthesis of myosin heavy chain in cultured muscle cells at micromolar concentrations’.

Small cytoskeletal-disrupting drug effects, cell-type specific, could be the kind of thing that would exacerbate some neurodegenerative conditions over time, depending on the particular causes. (I'm biased here, coming from more of a Huntington's standpoint (with BDNF and transport problems)) Although the NGF and MHC parts are there contextually, and thrown in for that paper with some ornithine stuff, it is certainly very limited. Which part of the cytoskeleton could be affected, which microtubule-associated proteins be dysregulated. What are alternative explanations?

Microtubules are fascinatingly regulated and associated/regulated in many ways and by many proteins (MAPs, the motor proteins, etc...). Neurons, amongst others, have the major MAP Tau, which is linked across many diseases, including Alzheimer's. Some sort of dysregulatory effect by a benzo the function of a protein could be problematic.

As such, the effect of midazolam on tau hyperphosphorylation in (Whittington et al, 2019) (human Tau in Mice) is troubling. If tau has increased difficulty binding to MTs, this cytoskeletal regulation could be a source of disruption or exacerbation of some neurodegenerative disease processes, depending on the etiology. (This study seems more in the anesthesia vein but I'd be curious about other benzodiazepines).

Disruptions in GABA-ergic signaling in Alzheimer's makes some of the receptors targets of study. It almost seems with excitotoxic and other elements that benzodiazepines could even be beneficial (weren't some of the y-secretase inhibitors based on benzos?)

Curious

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I mean, I don’t think there is critical toxicity, a coverup or even major effects, but when there are over 25 million prescriptions of alprazolam in the U.S. alone, and some possible associations, it makes you wonder. Especially if there would be a dose- or drug-dependent risk. As for COIs, well, that’s always a valid consideration between pharma, restrictive grants, and other care models.

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References

Benzodiazepine use and risk of dementia: prospective population based study
(Billioti de Gage et al., 2012) 10.1136/bmj.e6231

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia
(Ettcheto et al., 2020) 10.3389/fnagi.2019.00344

Anticholinergic and benzodiazepine medication use and risk of incident dementia: A UK cohort study
(Grossi et al., 2019) 10.1186/s12877-019-1280-2

Alterations in Brain-Derived Neurotrophic Factor in the Mouse Hippocampus Following Acute but Not Repeated Benzodiazepine Treatment
(Licata et al., 2013) 10.1371/journal.pone.0084806

Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease
(Moreno-Jiménez et al., 2019) 10.1038/s41591-019-0375-9

Peripheral-type benzodiazepines influence ornithine decarboxylase levels and neurite outgrowth in PC12 cells.
(Morgan et al., 1985)

The risk of Alzheimer's disease associated with benzodiazepines and related drugs: a nested case-control study
(Tapiainen et al., 2018) 10.1111/acps.12909

Differential effects of diazepam, tandospirone, and paroxetine on plasma brain-derived neurotrophic factor level under mental stress
(Tamaji et al., 2012) 10.1002/hup.2220

A benzodiazepine impairs the neurogenic and behavioural effects of fluoxetine in a rodent model of chronic stress
(Sun et al., 2013) 10.1016/j.neuropharm.2013.04.021

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice
(Zhao et al., 2012) 10.1016/j.bbr.2011.12.013

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As for the alcohol comparison, not quite sure I really follow. I think the lipid and vascular effects would probably play a greater role. Probably studies would follow similarly to heart disease.
Lower risk with some consumption compared to no consumption, and then higher with excess. Maybe some APOE modulation of effects/risk. ^HDL. [Not talking about alcohol related & Korsakoff's, of course.] Not really the same as benzos. I mean if benzos had a significant difference in lipid profiles over time, say decreased HDL and ^Tri, LDL, that could be interesting. Don't know the full association. If benzos fully matched alcohol or most effects were similarly GABAergic, wouldn't there be a more definitive decreased risk with some use of benzos (matching alcohol) rather than a possible dose dependent risk or minimal change? With benzo effects on BP and some sympathetic activity, you would almost expect a lower risk for say vascular dementia, rather than no risk or some risk.

I guess that is what intrigues me about a possible connection. With anticholinergics, the link with some dementias is easier to make. But with benzodiazepines it almost feels as if it should be the opposite, some decrease of risk, and that doesn't seem to be the case.

(Thinking about the neurosteroids like brexanolone, I wonder about the full connection of cholesterol to GABA systems. I mean clearly there is GABA-A affinity of some steroids at that level. But smaller steroidal vs lipoprotein complexes and interactions.)

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Yeah, man some places used/use so many drugs. Understaffed retirement places drugging up the old for compliance more than actual need. (Some of course need something but yes.) Sorry to hear that with your grandmother.

 

[Lil'LinaptkSix]

Yeah, do the cognitive effects (memory loss and whatever) have more insidious long-term consequences or is that more of an acute aspect.

Good question.
Guess there have been studies on this (surely). If an elderly person is on BZDs I can see why they cannot remember shit and get confused (as I do this on the daily at times): I actually enjoy it but then there is no one to tell me that something is wrong with me. I know there are plenty "wrong" with me and I'm good with it as well as those around me.
We know BZDs can cause a bit of *amnesia, even at low doses with occasional usage.
Again:

..., do the cognitive effects (memory loss and whatever) have more insidious long-term consequences or is that more of an acute aspect.

watdisis?

Increased risk of dementia is another major concern with long-term use of benzodiazepines. In a meta-analysis, heavy cumulative doses of benzodiazepines were associated with a risk of dementia and Alzheimer’s disease. Two other recent studies also suggested an association between benzodiazepine use and dementia, finding that heavy use increased risk of Alzheimer’s disease while occasional low-dose use did not.

Isn't this intuitive? Am I wrong in following up on benzo and Alzheimer's ? I mean they apparently doped these poor people up with "heavy cumulative doses of benzodiazepines" that "were associated with a risk of dementia and Alzheimer’s disease."
Shitttt... let me eat 20-30mg diaz and/or 4-8mg alp a day for a while and come ask me what my name is.... hahaha
Imma b hwoever you say I am....
Til im not.