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Univ., Diss.--Erlangen-Nürnberg, 1997.

Benzodiazepine dependence is a significant national problem. Although benzodiazepines — a class of drugs that includes drugs such as alprazolam, lorazepam, temazepam, clonazepam, and diazepam—have a wide range of uses including the treatment of insomnia, anxiety, and seizures; they are addictive. Individuals taking these drugs can quickly develop dangerous tolerances. Therefore, these drugs should not be selected as first choice nor used for more than short periods, yet a significant portion of the population uses benzodiazepines for long periods. This problem is significantly more pronounced in the elderly, a population that scholars have agreed should not use these drugs outside of extreme circumstances. Because benzodiazepines may be wrongfully perceived as an easy treatment for so many common afflictions, providers continue to prescribe them, and patients may be reluctant to discontinue use due to the symptoms associated with withdrawal (i.e., insomnia and anxiety). To avoid these symptoms, the standard discontinuation approach seen in an outpatient setting is a long-term taper that may take eight to 12 weeks of gradual reduction. However, in an inpatient setting, this long-term approach is unfeasible due to the short length of patient stays. The literature has given little consideration to this problem. Thus, it was necessary to review evidence and develop a guideline for benzodiazepine tapering in elderly patients receiving inpatient psychiatric care. The purpose of this project was to develop a guideline to taper benzodiazepines in the elderly using the Johns Hopkins Nursing Evidence-Based Practice Model (JHNEBP). The guideline was validated by expert peer reviewers using the AGREE II instrument. The completed guidelines offer recommendations on the tapering of benzodiazepines in an inpatient geropsych unit and best practices for interventions to increase the success rate of discontinuation.

Class of 2016 Abstract / Objectives: To describe the patterns of benzodiazepine use at a community health center in adults and to identify common demographic factors and chronic conditions that are associated with an increased usage rate. Subjects: Patients 18 years and older who had been treated at El Rio Community Health Center with an active benzodiazepine prescription on file. Methods: Data were collected from patient charts using a data collection form. Assessment included current benzodiazepine patients were taking, concurrent use of opiates and/or antispasmotics, indication for benzodiazepine use, concurrent medications for anxiety, depression, or insomnia, and prescriber type. Demographic data on age, gender, race, ethnicity, insurance type, and use of tobacco or alcohol were also collected. Results: Data were collected on 102 patients currently taking a benzodiazepine; 60 patients (mean age = 61.2, SD = 13.6) had concurrent first-line therapy for anxiety, depression, or insomnia and 42 patients (mean = 61.1, SD = 13.6) did not. There were a significantly higher proportion of women taking a benzodiazepine with first-line therapy than without first-line therapy (88.3% vs. 71.4%; p = 0.031). Additionally, higher proportion of benzodiazepine was prescribed with first-line therapy for depression than other indications (p = 0.002). Conclusions: More patients were prescribed benzodiazepines with concurrent first-line therapy for depression than other indications such as anxiety, insomnia, or other panic disorders. For this reason, health care professionals should be aware of the patterns of benzodiazepine use and comply with current recommended practice guidelines.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19890号 / 医博第4139号 / 新制||医||1016(附属図書館) / 32967 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 福原 俊一, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Ce travail doctoral a pour premier objectif de replacer les démences dans leur contexte de santé publique en estimant des projections de nombre de cas de démences en France et en Europe jusqu'en 2050. La sensibilité de ces projections aux changements d'hypothèses sur les valeurs d'incidence ou de mortalité des sujets déments, sur le scenario démographique utilisé, et sur la mise en place d'une intervention de prévention, a également été évaluée. Dans ce contexte de forte augmentation du nombre de cas à venir, la prévention des démences, qu'elle soit primaire ou secondaire, sera amenée à tenir une place primordiale dans la prise en charge sociétale de ce problème. Pour pouvoir aboutir à des résultats, les recherches en prévention primaire et secondaire ont besoin de s'appuyer sur une méthodologie adaptée et de sélectionner des critères de jugements pertinents. Le déclin cognitif semble être un critère de jugement de choix, mais son l'utilisation doit éviter un certain nombre d'écueils et de biais. Nous avons dans un premier temps illustré l'analyse de ce critère dans le cadre d'un questionnement de prévention primaire à l'aide d'un modèle non linéaire à variable latente pour données longitudinales. Nous avons pour cela étudié la relation entre consommation chronique de benzodiazépines et déclin cognitif, et montré l'absence d'association sur un large échantillon. Dans un second temps nous avons utilisé ce type de modèle pour décrire et comparer les propriétés métrologiques d'un large ensemble de tests neuropsychologiques dans une cohorte clinique de sujets atteints de déficit cognitif modéré (MCI), et pour étudier la sensibilité de ces tests aux changements cognitifs lié aux prodromes de la maladie d'Alzheimer. Nos travaux ont ainsi permis de fournir des arguments permettant de sélectionner des tests neuropsychologiques susceptibles d'être utilisés dans le cadre de recherches de prévention secondaire pour identifier et/ou suivre les patients présentant un déficit cognitif modéré (MCI) lié à une maladie d'Alzheimer. / The first aim of this doctoral work is to replace dementia in its public health context by estimating the number of dementia cases expected to occur in France and Europe over the next few decades until 2050. The sensitivity of these projections to hypotheses made on dementia incidence and mortality, demographic scenario used, and implementation of a prevention intervention, was also assessed. In this context of increasing number of future cases, the primary and secondary prevention of dementia will take a prominent place in the social management of this problem. Relevant research in the field of primary and secondary prevention requires an appropriate methodology and the use of relevant outcome. Cognitive decline seems to be an appropriate outcome, but a number of biases must be avoided. First, we illustrated the use of this criterion in the context of primary prevention using a nonlinear model with latent variable for longitudinal data to investigated the association between chronic use of benzodiazepines and cognitive decline. We showed the absence of association in a large population-based cohort. Secondly we used this model to describe and compare the metrological properties of a broad range of neuropsychological tests in a clinical cohort of patients with mild cognitive impairment (MCI). We also investigated the sensitivity of these tests to cognitive changes associated with prodromal Alzheimer's disease. Our work provides arguments for selecting neuropsychological tests which can be used in secondary prevention research, to identify and / or to follow patients with mild cognitive impairment (MCI) due to Alzheimer's disease.

There is accumulating evidence from many directions indicating that gender plays a critical role in drug abuse. Biological factors, including gonadal sex hormones, contribute in a significant although incompletely understood manner, to gender differences in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, GABAA receptor function is positively modulated by progesterone. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines, which also serve as positive modulators of GABAA receptors. The three studies presented here utilize within subject designs to assess the role of progesterone on the discriminative stimulus, subjective, performance and cardiovascular effects of triazolam, a short-acting benzodiazepine, in healthy, premenopausal women. The first study examined the effect of menstrual cycle phase on the discriminative stimulus effects of triazolam (0.00, 0.06, 0.12 and 0.25 mg/70 kg). The results of this study indicated that when progesterone levels peak (mid luteal phase), the discriminative stimulus effects of triazolam (0.12 mg/70 kg) are enhanced. The second study examined the separate and combined effects of a range of acute doses of oral micronized progesterone (0, 100 and 200 mg) and oral triazolam (0.00, 0.12 and 0.25 mg/70 kg) on the subjective, psychomotor and physiological effects of these medications, tested under conditions of low circulating sex hormones. The results of this study indicated that progesterone alone has some short-acting, sedative-like effects and enhances the subjective and performance effects of triazolam. The final study examined the effects of progesterone (0 and 100 mg) on the discriminative stimulus effects of triazolam (0.00, 0.06, 0.12 and 0.25 mg/70 kg), also under conditions of low circulating sex hormones. The results of this study indicated that the parent hormone progesterone does not appear to alter sensitivity to the discriminative stimulus effects of triazolam. Increases in sensitivity to triazolam in studies 1 and 2 may have been the result of neuroactive progesterone metabolites (e.g., allopregnanolone, TH-DOC), although future studies will be required to further examine this possibility. Taken together, these studies help clarify the manner in which the ovarian hormone progesterone and its metabolites modulate the behavioral effects of the benzodiazepines.

The experiments reported in this thesis studied the mechanisms of expression of overexpectation of conditioned fear, as measured by freezing. In Stage I, rats were conditioned to fear a tone and a flashing light conditioned stimulus (CS) through pairings with a 0.5 mA, 1 s shock. In Stage II, overexpectation was trained by the reinforcement of a compound of these CSs with a shock of the same magnitude. Two compound ?? shock pairings produced an overexpectation effect, as measured by freezing to presentations of the tone alone, while further Stage II training caused over-training of overexpectation. Expression of the overexpectation effect produced by two compound ?? shock pairings could be prevented by pre-test injection of the benzodiazepine partial inverse agonist FG7142. This effect was dose-dependent and not due to state-dependent memory. Control experiments suggested that it was also not due to any general effect of FG7142 on the Pavlovian freezing response. Freezing to a tone that had been conditioned, but not subjected to any decremental training procedures, was unaffected by administration of FG7142 before either the conditioning or test session. FG7142 also did not affect freezing to a tone that had been subjected to an associative blocking procedure. The hypothesis that overexpectation of conditioned fear may be context-dependent was also tested. However, renewal was not observed. Rats that received Stage II training in a context distinct from the Stage I training context showed equivalent expression of overexpectation regardless of whether testing was conducted in the Stage I or Stage II training context. These results are consistent with the hypothesis that overexpectation, like extinction, leads to the imposition of a GABAA receptor-mediated mask on the fear CR. Moreover, they suggest that this masking of fear is the specific consequence of negative predictive error.

The main study purposes were to determine: whether antidepressant (AD) use increases the risk of type 2 diabetes mellitus; and whether results differ when using different methodological designs: retrospective cohort design and nested case-control design. A retrospective Texas Medicaid database analysis of new AD (exposed cohort) and benzodiazepine (unexposed cohort [BZ]) users from January 1, 2002 to December 31, 2009 was conducted. Patients aged 18-64 years without diabetes at cohort entry were included. The primary outcome was incident diabetes and the main independent variable was AD vs. BZ use. Covariates included age, gender, race/ethnicity, medication adherence, persistence, number of concomitant diabetogenic medications, Chronic Disease Score, treatment duration, year of cohort entry, and use of both AD and BZ at index. Regression analyses (adjusted) were used to address the study purposes. Of the study cohort (N=44,715), 35,552 (79.5%) were AD users and 9,163 (20.5%) were BZ users. Patients were followed for an average of 2.3±1.9 years (Median=1.8 years), were on average 38.6±14.2 years old, and 69.3% were female. Using the retrospective cohort design, AD use was associated with a 48.9% increase (logistic regression) and 60.0% increase (Cox regression) in the risk of diabetes compared to BZ use (logistic regression analysis: RR[subscript adj]. =1.489; 95% CI: 1.331-1.667; Cox regression analysis: HR[subscript adj]. =1.600; 95% CI: 1.437 - 1.783). Using a nested case-control design within the entire study cohort, AD use was associated with a 54.1% increase in the risk of diabetes compared to BZ use (OR[subscript adj]. =1.541; 95% CI: 1.368 - 1.735). Using a nested case-control design within the exposed cohort, current AD use was associated with a two-fold higher risk of diabetes compared to former AD use (OR[subscript adj]. =1.995; 95% CI: 1.759 - 2.264). Among antidepressant classes, TCAs, SSRIs, SNRIs, and Other ADs were associated with a higher diabetes risk compared with BZs. The results from the present study suggest that AD use is associated with an increased risk of diabetes. Clinicians may need to take this into account when choosing treatment for depression in patients at high risk of diabetes. / text

The experiments reported in this thesis studied the mechanisms of expression of overexpectation of conditioned fear, as measured by freezing. In Stage I, rats were conditioned to fear a tone and a flashing light conditioned stimulus (CS) through pairings with a 0.5 mA, 1 s shock. In Stage II, overexpectation was trained by the reinforcement of a compound of these CSs with a shock of the same magnitude. Two compound ?? shock pairings produced an overexpectation effect, as measured by freezing to presentations of the tone alone, while further Stage II training caused over-training of overexpectation. Expression of the overexpectation effect produced by two compound ?? shock pairings could be prevented by pre-test injection of the benzodiazepine partial inverse agonist FG7142. This effect was dose-dependent and not due to state-dependent memory. Control experiments suggested that it was also not due to any general effect of FG7142 on the Pavlovian freezing response. Freezing to a tone that had been conditioned, but not subjected to any decremental training procedures, was unaffected by administration of FG7142 before either the conditioning or test session. FG7142 also did not affect freezing to a tone that had been subjected to an associative blocking procedure. The hypothesis that overexpectation of conditioned fear may be context-dependent was also tested. However, renewal was not observed. Rats that received Stage II training in a context distinct from the Stage I training context showed equivalent expression of overexpectation regardless of whether testing was conducted in the Stage I or Stage II training context. These results are consistent with the hypothesis that overexpectation, like extinction, leads to the imposition of a GABAA receptor-mediated mask on the fear CR. Moreover, they suggest that this masking of fear is the specific consequence of negative predictive error.