Long-Term use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders

Michelini, S.; Cassano, G.B.; Frare, Franco; Perugi, Giulio

doi:10.1055/s-2007-979558

Cited by 117 publications

(84 citation statements)

References 28 publications

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“…Although effective treatments are available, we are still meeting very modest success in curing these disorders, largely due to unknown molecular and neuronal mechanisms (1,2). In addition, most available medications have certain side effects or problems with tolerance or dependency (3,4). Therefore, it is of significant interest to further explore mechanisms to develop a novel therapeutic strategy.…”

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confidence: 99%

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Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Chen

Nakajima

Meacham

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic ''tone,'' which is largely determined by the expression level of the CCKR-2. Using the tTA͞tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular͞ neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity.behaviors ͉ transgenic mouse

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confidence: 99%

“…Selective CCKR-2, but not -1, agonists produce anxiogenic effects (2,17). Selective CCKR-2 agonists can provoke or facilitate panic-like anxiety, and this effect can be blocked by CCKR-2, but not -1, antagonists (3,5,18). Selective CCKR-2, but not -1, antagonists produce anxiolytic effects (19).…”

mentioning

confidence: 99%

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Chen

Nakajima

Meacham

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…"to get high") are the most commonly reported motives for prescription drug misuse (86, 87). Self-medication, where medicines are used without medical supervision to alleviate symptoms of mental symptoms such as stress and anxiety, may be an important motive of psychoactive prescription drug misuse across groups in the general population of today (88)(89)(90).…”

Section: Psychoactive Prescription Drug Misuse and Abusementioning

confidence: 99%

Psychoactive prescription drug use disorders, misuse and abuse : Pharmacoepidemiological aspects

Tjäderborn

2016

Linköping University Medical Dissertations

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Background: There is a widespread and increasing use of psychoactive prescription drugs, such as opioid analgesics, anxiolytics, hypnotics and anti-epileptics, but their use is associated with a risk of drug use disorder, misuse and abuse. Today, these are globally recognised and emerging public health concerns. Aim:The aim of this thesis is to estimate the occurrence and prevalence of psychoactive prescription drug use disorders, misuse and abuse, and to investigate the association with some potential risk factors. Methods:A study using register data from forensic cause of death investigations analysed and described cases of fatal unintentional intoxications with tramadol (Study I). Based on register data on spontaneously reported adverse drug reactions (ADRs) reported cases of tramadol dependence were scrutinized and summarised (Study II). In a study in suspected drug-impaired drivers with a toxicology analysis confirming intake of tramadol, diazepam, flunitrazepam, zolpidem and zopiclone, the prevalence of non-prescribed use was assessed and associated factors were investigated (Study III). From a national cohort of patients initiating prescribed treatment with pregabalin, identified using data on prescription fills, a study investigated longitudinal utilisation patterns during five years with regards to use above the maximum approved daily dose (MAD) of the drug, and factors associated with the utilisation patterns (Study IV).Results: In the first study, 17 cases of unintentional intoxications were identified, in which tramadol was judged to have caused or contributed to the death. Of the deceased, more were men, the median age was 44 years and the majority used multiple psychoactive substances (prescription drugs, alcohol and/or illicit drugs). In the second study, 104 spontaneously vi reported cases of possible or probable tramadol dependence were identified, of which more concerned women. The median age in these cases was 45 years and in about a third of cases the person had a history of substance abuse and in 40% of cases there was documented history of psychoactive medication use. Severe addiction was reported. In the third study, more than half of the individuals suspected of drug-impaired driving used the drug without a recent prescription.Non prescribed use was most frequent in users of benzodiazepines and of tramadol compared to users of zolpidem or zopiclone, and was more likely in younger individuals and in multiplesubstance users and less likely in individuals with a recent prescription for another psychoactive medication. In the last paper, five longitudinal utilisation patterns were found in pregabalin users, with two patterns associated with a particularly high risk of use of doses above the maximum approved daily dose. The highest risk of use of daily doses above the MAD over time was associated with male sex, younger age, non-urban residency, and a recent prescribed treatment with an antiepileptic or opioid analgesic drug. Conclusions

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“…Lader and Morton [18] estimated the incidents of these adverse reactions to be about 5%, even in case of short-term use. The paradoxical reactions may consist of depression, with or without suicidal tendencies, phobias, violent behavior and symptoms sometimes misdiagnosed as psychosis [19]. Anxiolytics sometimes cause memory loss (i.e.…”

Section: Medical Treatment Of Burnoutmentioning

confidence: 99%

The medical perspective on burnout

Kakiashvili

Leszek

Rutkowski

2013

International Journal of Occupational Medicine and Environmental Health

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Objective: The aim of this study was to review recent medical findings related to burnout, its diagnosis, treatment, characteristic pathophysiological features, and preventive measures. Materials and Methods: A systematic review of the scientific literature in PubMed/Medline was performed. The most recent and important findings were reported. Results: Burnout was found to be a risk factor for myocardial infarction and coronary heart disease. It was also related to reduced fibrinolytic capacity, decreased capacity to cope with stress and hypothalamic-pituitary-adrenal (HPA) axis hypoactivity. Severe burnout symptoms are associated with a lower level or smaller increase of the cortisol awakening response (CAR), higher dehydroepiandrosterone-sulphate (DHEAS) levels, lower cortisol/DHEAS ratios and stronger suppression as measured by the dexamethasone suppression test (DST). More and more literature works suggest that the evaluation of the HPA axis should be brought to the attention of primary care physicians. There is no universal agreement on specific treatment and diagnostic measures to evaluate the wide range of HPA axis disorders. The cost-effective evaluation of adrenal hormones via saliva samples by a primary care physician may significantly alter the course of therapy in numerous chronic disease patients. Psychiatric disorders may have similar symptoms, but they have distinctive hormonal profiles. Having burnout recognized as a medical condition would help in differentiating burnout from similar clinical syndromes, such as depression or anxiety, and provide appropriate treatment to burnout patients. Proper treatment is essential for a fast and full recovery. Conclusion: Chronic stress-related disorders often fall outside the category of a "true" disease and are often treated as depression or not treated at all. The evaluation of adrenal hormones via saliva samples helps to predict burnout. Burnout screening techniques, dietary and nutritional guidelines and lifestyle changes for supporting the HPA function need to be developed. The presented material includes hormonal, dietary, and pharmaceutical perspectives.

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Long-Term use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders

Cited by 117 publications

References 28 publications

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Psychoactive prescription drug use disorders, misuse and abuse : Pharmacoepidemiological aspects

The medical perspective on burnout

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