Benzodiazepine use and risk of Alzheimer’s disease

Posted on October 10, 2015 by Maurice Preter MD

Benzodiazepine use and risk of Alzheimer’s disease

Benzodiazepine use and risk of Alzheimer’s disease: case-control study

BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g5205 (Published 09 September 2014)Cite this as: BMJ 2014;349:g5205 

  1. Sophie Billioti de Gage, PhD student1,
  2. Yola Moride, professor23,
  3. Thierry Ducruet, researcher2,
  4. Tobias Kurth, director of research45,
  5. Hélène Verdoux, professor16,
  6. Marie Tournier, associate professor16,
  7. Antoine Pariente, associate professor1,
  8. Bernard Bégaud, professor1

Author affiliations

  1. Correspondence to: S Billioti de Gage sophie.billioti-de-gage@u-bordeaux.fr
  • Accepted 4 August 2014

Abstract

Objectives To investigate the relation between the risk of Alzheimer’s disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment.

Design Case-control study.

Setting The Quebec health insurance program database (RAMQ).

Participants 1796 people with a first diagnosis of Alzheimer’s disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.

Main outcome measure The association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life.

Results Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).

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.

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Benzodiazepine use associated with increased risk of dementia.

Posted on October 10, 2015 by Maurice Preter MD

Benzodiazepine use is associated with increased risk of dementia. More evidence emerging.

Research

Benzodiazepine use and risk of dementia: prospective population based study

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6231 (Published 27 September 2012)Cite this as: BMJ 2012;345:e6231 

  1. Sophie Billioti de Gage, PhD student12,
  2. Bernard Bégaud, professor123,
  3. Fabienne Bazin, researcher12,
  4. Hélène Verdoux, professor124,
  5. Jean-François Dartigues, professor153,
  6. Karine Pérès, researcher15,
  7. Tobias Kurth, director of research167,
  8. Antoine Pariente, associate professor123

Author affiliations

  1. Correspondence to: S Billioti de Gage or B Bégaud, Université Bordeaux Segalen, INSERM U657, 146 rue Léo Saignat, F-33076, Bordeaux cedex, France sophie.billiotidegage@u-bordeaux2.fr or bernard.begaud@u-bordeaux2.fr
  • Accepted 4 September 2012

Abstract

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 at least the third year of follow-up.

Main outcome measures Incident dementia, confirmed by a neurologist.

Results During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users.

Conclusions In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.

Benzodiazepine use associated with increased risk of dementia Link: http://www.bmj.com/content/345/bmj.e6231 

 

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Preter Klein Panic disorder theory now available on PubMed Central (PMC)

Posted on October 2, 2015 by Maurice Preter MD

[nihms] Manuscript #585187: Your manuscript is available in PMC

Dear Maurice Preter,

Manuscript NIHMS585187 (“Lifelong opioidergic vulnerability through early life separation: A recent extension of the false suffocation alarm theory of panic disorder”) has been loaded into PubMed Central (PMC) and made available for public access:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195810

The submission process for this manuscript is now complete.

We encourage you to make further manuscript submissions as they become eligible. As always, please feel free to contact the NIHMS Help Desk with any questions at http://www.nihms.nih.gov/db/sub.cgi?page=email.

Thank you for using the NIHMS system.

Sincerely,

The NIHMS Help Desk

Panic disorder theory (excerpt):

“In conclusion, we objectively, experimentally showed a physiological link between endogenous opioid system deficiency and panic-like suffocation sensitivity in healthy adults. This is consonant with the expanded Suffocation-False Alarm theory of panic suggesting an episodic functional endogenous opioid deficit (Preter and Klein, 1998). The specificity of the naloxone+lactate model of clinical panic should be tested using specific anti-panic components, possibly including opioidergic mixed agonist-antagonists such as buprenorphine. If specific, the naloxone+lactate effect in normal humans affords a screening method for testing putative anti-panic drugs which is currently not available. This could obviate the experimental treatment of panic disorder patients in drug development.

Our data also show for the first time that actual separations and losses during childhood, such parental death, parental separation or divorce (CPL), effect lifelong alterations in the physiological reactivity of the endogenous opioid system of healthy adults.

This result encourages epigenetic inquiry into the effects of CPL on endogenous opioid systems, and their role in resilience under extreme stress. In addition, a redefinition of what constitutes a (truly) healthy control in clinical research protocols may be called for.”

 

 

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Neuroprotective and disease-modifying effects of the ketogenic diet

Posted on June 28, 2015 by Maurice Preter MD
PMCID: PMC2367001
NIHMSID: NIHMS42857

Neuroprotective and disease-modifying effects of the ketogenic diet

The publisher’s final edited version of this article is available at Behav Pharmacol
See other articles in PMC that cite the published article.

Abstract

The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, and may also be protective in traumatic brain injury and stroke. These observations are supported by studies in animal models and isolated cells that show that ketone bodies, especially β-hydroxybutyrate, confer neuroprotection against diverse types of cellular injury. This review summarizes the experimental, epidemiological and clinical evidence indicating that the ketogenic diet could have beneficial effects in a broad range of brain disorders characterized by the death of neurons. Although the mechanisms are not yet well defined, it is plausible that neuroprotection results from enhanced neuronal energy reserves, which improve the ability of neurons to resist metabolic challenges, and possibly through other actions including antioxidant and anti-inflammatory effects. As the underlying mechanisms become better understood, it will be possible to develop alternative strategies that produce similar or even improved therapeutic effects without the need for exposure to an unpalatable and unhealthy, high-fat diet.

Keywords: Alzheimer’s disease, cellular energetics, epilepsy, ketone bodies, ketogenic diet, mitochondria, neuroprotection, Parkinson’s disease, stroke, traumatic brain injury
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Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects.

Posted on June 26, 2015 by Maurice Preter MD

Neurology. 2005 May 24;64(10):1704-11.

Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects.

Abstract

OBJECTIVES:

To determine the rate of brain atrophy in neurologically asymptomatic elderly and to investigate the impact of baseline variables including conventional cerebrovascular risk factors, APOE epsilon4, and white matter hyperintensity (WMH) on its progression.

METHODS:

We assessed the brain parenchymal fraction at baseline and subsequent annual brain volume changes over 6 years for 201 participants (F/M = 96/105; 59.8 +/- 5.9 years) in the Austrian Stroke Prevention Study from 1.5-T MRI scans using SIENA (structural image evaluation using normalization of atrophy)/SIENAX (an adaptation of SIENA for cross-sectional measurement)(www.fmrib.ox.ac.uk/fsl). Hypertension, cardiac disease, diabetes mellitus, smoking, and regular alcohol intake were present in 64 (31.8%), 60 (29.9%), 5 (2.5%), 70 (39.3%), and 40 (20.7%) subjects, respectively. Plasma levels of fasting glucose (93.7 +/- 18.6 mg/dL), glycated hemoglobin A (HbA1c; 5.6 +/- 0.7%), total cholesterol (228.3 +/- 40.3 mg/dL), and triglycerides (127.0 +/- 75.2 mg/dL) were determined. WMH was rated as absent (n = 56), punctate (n = 120), early confluent (n = 14), and confluent (n = 11).

RESULTS:

The baseline brain parenchymal fraction of the entire cohort was 0.80 +/- 0.02 with a mean annual brain volume change of -0.40 +/- 0.29%. Univariate analysis demonstrated a higher rate of brain atrophy in older subjects (p = 0.0001), in those with higher HbA1c (p = 0.0001), higher body mass index (p = 0.02), high alcohol intake (p = 0.04), severe WMH (p = 0.03), and in APOE epsilon4 carriers (p = 0.07). Multivariate analysis suggested that baseline brain parenchymal fraction, HbA1c, and WMH score explain a major proportion of variance in the rates of brain atrophy in the cohort (corrected R2 = 0.27; p = 0.0001).

CONCLUSIONS:

Neurologically asymptomatic elderly experience continuing brain volume loss, which appears to accelerate with age. Glycated hemoglobin A (HbA1c) was identified as a risk factor for a greater rate of brain atrophy. Clustering of factors associated with the so-called metabolic syndrome in subjects with high HbA1c suggests a link between this syndrome and late-life brain tissue loss.

PMID:

 

15911795

 

[PubMed – indexed for MEDLINE] 
Posted in Aging, China, dietary, epigenetics, Events, Fifth Avenue Concierge Medicine, Forensic Neuropsychiatry, Health, keto, News, Psychiatry/Neurology | Tagged , , , , |