The treatment of benzodiazepine dependence

Withdrawal of benzodiazepines is currently advised for long-term benzodiazepine users because of doubts about continued efficacy, risks of adverse effects, including dependence and neuropsychological impairment and socio-economic costs. About half a million people in the UK may need advice on withdrawal. Successful withdrawal strategies should combine gradual dosage reduction and psychological support. The benzodiazepine dosage should be tapered at an individually titrated rate which should usually be under the patient's control. The whole process may take weeks or months. Withdrawal from diazepam is convenient because of available dosage strengths, but can be carried out directly from other benzodiazepines. Adjuvant medication may occasionally be required (antidepressants, propranolol) but no drugs have been proved to be of general utility in alleviating withdrawal-related symptoms. Psychological support should be available both during dosage reduction and for some months after cessation of drug use. Such support should include the provision of information about benzodiazepines, general encouragement, and measures to reduce anxiety and promote the learning of non-pharmacological ways of coping with stress. For many patients the degree of support required is minimal; a minority may need counselling or formal psychological therapy. Unwilling patients should not be forced to withdraw. With these methods, success rates of withdrawal are high and are unaffected by duration of usage, dosage or type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history or personality disorder. Longer-term outcome is less clear; a considerable proportion of patients may temporarily take benzodiazepines again and some need other psychotropic medication. However, the outcome may be improved by careful pharmacological and psychological handling of withdrawal and post-withdrawal phases.     

Group Treatment of Benzodiazepine Dependence

Sixteen patients referred for withdrawal from their chronic benzodiazepine usage were treated over a 28-week period using a primarily cognitive approach in a group or on an individual basis using telephone contact. The withdrawal regime was individually tailored for each patient according to the intensity of withdrawal symptoms. Anxiety management and cognitive restructuring techniques were used to help patients relabel their withdrawal symptoms as cues for the implementation of coping strategies. Patients in both groups were successful in reducing their intake over the treatment period but patients treated in the group showed lower attrition rates and better long-term outcome. Withdrawal symptoms, anxiety and depression improved alongside the reduction in drug intake and improvements were maintained at a 3 month and 1 year follow-up.     

Benzodiazepine Withdrawal: outcome in 50 patients

Clinical outcome was assessed in SO consecutive patients who completed a course of supervized benzodiazepine withdrawal following referral to a Clinical Pharmacology Unit. The patients had been taking prescribed benzodiazepines regularly for 1–22 years and all wished to stop. On presentation, all had many symptoms which they attributed to benzodiazepines. The outcome 10 months to 3.S years later was judged as excellent (fully recovered) in 48%, good (much better) in 22%, moderate (better) in 16% and poor (no better) in 6%. One patient failed to withdraw and three relapsed onto benzodiazepine use after withdrawal. Younger age was significantly associated with a favourable outcome, but outcome was not related to duration or dosage of benzodiazepines, type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history, marital status, or sex.     

The Outcome of Outpatient Withdrawal from Alcohol

A sample of 50 male military veterans, many of whom were heavily alcohol dependent, was studied in an outpatient withdrawal programme. Fifty-four per cent of the sample completed outpatient withdrawal, 22% were admitted to inpatient care and 24% dropped out from care. The ‘admitted’ group was distinguishable by a later age of onset of drinking and by higher dependence scores (SADQ) than the other two groups, and by higher daily cigarette consumption than the ‘completed’ group. Predictive factors for the group which dropped out from care could not be identified, though there was a trend for these patients to be younger, and none of them presented with a serious physical disorder. Four risk factors, including SADQ score, were selected which had some predictive value for admission to inpatient care.     

Anxiolytics and sedative/hypnotics dependence

Anxiolytics and sedative/hypnotics are commonly used drugs. Benzodiazepines have largely replaced barbiturate and non-barbiturate anxiolytics and sedative/hypnotics as they are as effective and safer. Experiments in laboratory animals have shown that chronic administration of benzodiazepines tested to date can induce physical dependence. The severity of the withdrawal syndrome is clearly related to the dose, duration of administration and elimination rate of the drugs. It is now also clear that high doses of barbiturates and benzodiazepines can induce physical dependence in humans. In addition, a withdrawal syndrome after discontinuation of chronic benzodiazepine therapeutic treatment, with and without tolerance, has been well characterized. Symptoms may resemble those of anxiety or ‘rebound’ phenomena but some are typical of withdrawal. A relationship between benzodiazepine discontinuation and self-administration has been well documented. Negative reinforcement associated with a reduction of withdrawal symptoms may play a role supporting persistent benzodiazepine use.     

Agonist substitution—a treatment alternative for high‐dose benzodiazepine‐dependent patients?

There is vast evidence for the superiority of agonist treatments (methadone, buprenorphine) over a withdrawal approach in opioid‐dependent populations. Little research, however, has been conducted on the same approach for the treatment of high‐dose benzodiazepine (BZD) dependence. Even large‐scale reviews and meta‐analyses discussing treatment strategies for benzodiazepine‐dependent patients focus solely upon approaches that aim at achieving abstinence, namely on complete BZD withdrawal. While the types of interventions differ (e.g. gradual benzodiazepine taper with a long or a short half‐life benzodiazepine, switching to non‐benzodiazepine anxiolytics or prescribing adjunctive medications such as antidepressants or anticonvulsants on an in‐ or out‐patient basis), the common aim of treatment still is total abstinence from benzodiazepines. However, the majority of patients suffering from high‐dose BZD dependence do not succeed with long‐term abstinence, irrespective of the procedure, and clinicians have been using BZD ‘substitution’ treatment in such cases for decades. Therefore, we suggest the evaluation of a substitution approach in this group, consisting of maintenance treatment with a slow‐onset, long‐acting BZD. Advantages of such a procedure may be improved health, less craving, fewer withdrawal complications, reduced anxiety, increased treatment retention, improvements in social functioning and less illegal activity. Cognitive impairments, the most problematic side effects of substitution treatment with benzodiazepines, could possibly be minimized by using an optimal agonist.     

Alcohol withdrawal syndrome management: Is there anything new?

Patients with alcohol use disorder experience frequently alcohol withdrawal syndrome (AWS), which is a potentially life-threatening condition mainly caused by glutamate overactivity. The aim of therapeutic alcohol withdrawal is the entry into a process of complete and lasting abstinence. Therefore preparing withdrawal is crucial to optimize compliance and efficacy of aftercare. Indeed, performing repeated withdrawal per se without any project of subsequent abstinence may be deleterious, at least because of repeated exposure to glutamate neurotoxicity. Managing AWS mainly consists in anticipating severe withdrawal, decreasing the risk of complications, making this experience as comfortable as possible, preventing from long-term benzodiazepine use, and enhancing motivation to aftercare and long-term abstinence. In particular, there are specific guidelines to choose which benzodiazepine administration approach to adopt (i.e. symptom-triggered, fixed schedule or loading dosage) and which other drugs to deliver (e.g. thiamine, folate, magnesium). Specific precautions should be taken in the elderly.     

Biological processes in benzodiazepine dependence

The indications for the benzodiazepines include anxiety, insomnia, muscle spasm and epilepsy and each disorder has a variety of biological substrates. Limbic structures and the neurotransmitters noradrenaline, 5-HT and GABA have all been implicated. Benzodiazepines act on alloosteric receptor sites and potentiate the actions of GABA in modulating chloride ionophores across nerve membranes. These effects can be blocked by the benzodiazepine antagonist, flumazenil. The molecular pharmacology of the benzodiazepine-GABA-chloride receptor is complex, with a wide range of different subunits. Animal models of dependence have suggested that the changes associated with long-term benzodiazepine use are related more to receptor-effector coupling than to the receptor characteristics themselves. Thus, benzodiazepine agonists on long-term use lose their efficacy, antagonists become partial inverse antagonists, and inverse agonists increase in efficacy. Various clinical implications are explored, including the use of flumazenil to prevent and to treat benzodiazepine withdrawal syndromes.     

Depression underdiagnosis and the effects on quality of life in outpatients with HIV at a Nigerian university teaching hospital

The study aimed to determine the frequency of depressive disorder in a sample of patients with HIV and its level of underdiagnosis by attending physicians. The study also explored the effect of depressive disorder on the quality of life (QOL) of patients with HIV. A sociodemographic questionnaire was administered to patients with HIV attending a medical out-patient clinic at Ahmadu Bello University Teaching Hospital, central northern Nigeria. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to screen for depressive symptoms, and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) was used to confirm the diagnosis of depressive disorder. The patients’ medical records were screened for documentation of depressive symptoms or previous treatment with antidepressants by an attending physician. The World Health Organization Quality of Life assessment short version (WHOQOL-BREF) was used to measure six domains of QOL. A total of 310 patients with HIV participated in the study; of these, 14.2% (n = 44) met the diagnostic criteria for depressive disorder, according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). All of these cases of depressive disorder had not been previously recognised by any attending physician. Of the 310 participants, 58 (18.7%) had a ‘poor’ score and 252 (81.3%) had an ‘average or above’ score for overall QOL. Of the 44 with depressive disorder, 28 (63.6%) were among those with a poor score for overall QOL. A fairly similar pattern was observed for all the other domains, with patients with depressive disorder accounting for greater proportions of the participants with poor domain scores. Thus, the authors found that depression is common but seldom clinically recognised in people with HIV, and that it is associated with a reduction in quality of life. Identifying and treating depression in patients with HIV will improve functioning and general wellbeing.     

A training program to enhance recognition of depression in nursing homes,assisted living,and other long-term care settings: Description and evaluation

ABSTRACT

Low levels of symptom recognition by staff have been “gateway” barriers to the management of depression in long-term care. The study aims were to refine a depression training program for front-line staff in long-term care and provide evaluative knowledge outcome data. Three primary training modules provide an overview of depression symptoms; a review of causes and situational and environmental contributing factors; and communication strategies, medications, and clinical treatment strategies. McNemar’s chi-square tests and paired t-tests were used to examine change in knowledge. Data were analyzed for up to 143 staff members, the majority from nursing. Significant changes (p < .001) in knowledge were observed for all modules, with an average change of between 2 and 3 points. Evidence was provided that participants acquired desired information in the recognition, detection, and differential diagnosis and treatment strategies for those persons at significant risk for a depressive disorder.     

Late life depression: challenge or curse for the general practitioner (GP). A cohort study

The aim of this study was to examine specificity of GP's care for elderly depressed patients. Among 17,000 examinees (10 GP-Offices) were extracted 231 patients with diagnosis of depressive episode (F32) and 152 with diagnosis of recurrent depressive disorder (F33) classified according to ICD-10. Older than 65 years were 134 depressed patients. Data were tracked longitudinally and obtained retrospectively for a 1-year period from 1st January to 31st December 2008. Questionnaire was designed for this study to estimate the care delivered to depressed patients. Logistic regression analysis showed that GP more often diagnosed depression in older patients, provided medical care for them and changed their therapy. The main therapy for up to 80% of elderly with diagnosis of recurrent depressive disorder was combination of pharmacotherapy and GP's support and psychiatrist psychotherapy, while more than 20% of elderly with diagnosis of depressive episode took only pharmacotherapy. In comparison with younger age group, elderly less frequently received psychotherapy and GP's support. GP has an important role in older depressed patient care, so improvement efforts could focus on GP's clinical skills of depression treatment, as well as therapy effectiveness and depression outcome for understanding treatment specificity within elderly.     

Psychopathology in patients with endogenous Cushing's syndrome: 'atypical' or melancholic features

OBJECTIVE Prolonged elevations of glucocorticoids have been linked to the affective disturbances experienced by patients with Cushing's syndrome. Major depression has been most commonly reported In patients with endogenous Cushing's syndrome. The purpose of this study was to determine whether these patients experience melancholic or ‘atypical’ subtype depression and to determine relations between current psychological functioning and factors such as duration and severity of Cushing's syndrome. DESIGN AND PATIENTS We examined 33 adult patients with documented Cushing's syndrome and 17 hospitalized, matched controls, using standardized structured interviews and tests. RESULTS During the active phase of Cushing's syndrome (prior to and/or on admission), 66.7% of all patients reported histories meeting criteria for a psychiatric diagnosis. Of those with a diagnosis during Cushing's syndrome, 50% reported major depression. Upon presentation to this institution, atypical depression was the most common diagnosis involving 51.5% (n= 17) of ail enrolled patients. Of the 17 with atypical depression, 8 reported a co-morbid psychiatric disorder. The duration of Cushing's syndrome was an Important factor in predicting whether patients sought psychological Intervention or met criteria for psychiatric diagnosis. CONCLUSION Patients with active endogenous Cushing's syndrome exhibit significant psychopathology expressed primarily by atypical depression. Longer duration of Cushing's syndrome may place them at increased risk of such psychopathology.     

Psychological Profile of Social Drinkers

In a cross-sectional study, the psychological profile of light social drinkers was compared with that of heavy social drinkers and alcohol-dependent patients who showed no evidence of clinical depression. The selection of psychological tests was based on the hypothesis that alcohol abuse and depression may sometimes be different expressions of the same disorder, and that the relationship between the two disorders may in pan be explicable in terms of shared psychological vulnerability factors. The tyests chosen were those thought most likely to predict vulnerability to depression. Dependent patients demonstrated significantly greater distortion of cognitive style than heavy social drinkers, who in turn rated significantly higher than light drinkers. Heavy social drinkers occupied a middle ground with regard to psychological profile between light drinkers and ‘alcoholics’, sharing some attributes with each. Possible implication for interventions by general practitioners are discussed.     

Exploring the association between cannabis use and depression

Aim To examine the evidence on the association between cannabis and depression and evaluate competing explanations of the association. Methods A search of Medline, Psychinfo and EMBASE databases was conducted. All references in which the terms ‘cannabis’, ‘marijuana’ or ‘cannabinoid’, and in which the words ‘depression/depressive disorder/depressed’, ‘mood’, ‘mood disorder’ or ‘dysthymia’ were collected. Only research studies were reviewed. Case reports are not discussed. Results There was a modest association between heavy or problematic cannabis use and depression in cohort studies and well‐designed cross‐sectional studies in the general population. Little evidence was found for an association between depression and infrequent cannabis use. A number of studies found a modest association between early‐onset, regular cannabis use and later depression, which persisted after controlling for potential confounding variables. There was little evidence of an increased risk of later cannabis use among people with depression and hence little support for the self‐medication hypothesis. There have been a limited number of studies that have controlled for potential confounding variables in the association between heavy cannabis use and depression. These have found that the risk is much reduced by statistical control but a modest relationship remains. Conclusions Heavy cannabis use and depression are associated and evidence from longitudinal studies suggests that heavy cannabis use may increase depressive symptoms among some users. It is still too early, however, to rule out the hypothesis that the association is due to common social, family and contextual factors that increase risks of both heavy cannabis use and depression. Longitudinal studies and studies of twins discordant for heavy cannabis use and depression are needed to rule out common causes. If the relationship is causal, then on current patterns of cannabis use in the most developed societies cannabis use makes, at most, a modest contribution to the population prevalence of depression.     

Oxcarbazepine in Rapid Benzodiazepine Detoxification

Objective: This study aims at evaluating the tolerability and efficacy of the antiepileptic drug oxcarbazepine in benzodiazepine detoxification in ten patients. Methods: In this case study of an inpatient withdrawal program, each of the ten patients was detoxified using oxcarbazepine and completed withdrawal successfully without the occurrence of withdrawal symptoms. The detoxification program followed an outlined dosage scheme with oxcarbazepine increase and benzodiazepine tapering. Results: The rapidity of benzodiazepine detoxification using oxcarbazepine was remarkable, benzodiazepine withdrawal being completed in as little as 11 days. Conclusions: The results support the assumption that oxcarbazepine is a valuable drug for inpatient benzodiazepine withdrawal programs.     

Prognostic value of thyrotropin receptor antibodies (TRAb) in Graves' disease: a 120 months prospective study

In most trials, at least 30-60% of patients with Graves' disease treated with antithyroid drugs relapse within 2 years after therapy withdrawal. At present, there are no prognostic parameters available early in treatment to indicate patients likely to achieve long-term remission. Because thyrotropin receptor autoantibodies (TRAb) are specific for Graves' disease, we evaluated the ability of their levels and of their rate of change to predict long-term prognosis. In our study 216 consecutive patients with newly diagnosed Graves' disease started a therapy with methimazole. Patients were treated until they achieved euthyroidism and TRAb were measured at 6-month intervals throughout a follow up of 120 months. Our study demonstrated that at the onset of hyperthyroidism patients' age, sex, fT4 levels and goiter size had no prognostic value in predicting long-term prognosis (respectively p = 0.79; p = 0.98; p = 0.83; p = 0.89). On the contrary, at the time of diagnosis TRAb titer was a good predictor of the final outcome (p<0.001); a titer equal to (or) more than 46.5 UI/L could identify patients who had never achieved long-term remission with a sensitivity of 52% and a specificity of 78%. Also fall rate of TRAb at 6 months of follow up and after therapy withdrawal were useful to predict the final outcome (p<0.001). At 6 months of follow up the time of therapy withdrawal, a decrease of TRAb lower than 52.3% or even its increase could identify patients who had never achieved permanent remission with a sensitivity of 55% and a specificity of 79.1%. No single parameter among TRAb, satisfactory identified a sub-set of patients who achieved long remission. Accordingly to our data, the best result in predicting long term remission is probably given by the presence of at least one of the two features evaluated at 6 months (TRAb titer and/or percentage of TRAb fall rate), with a sensitivity of 63% and specificity of 88%. TRAb titers evaluated both at the onset of hyperthyroidism that at 6 months of therapy or their rate of fall at 6 months and at ATD withdrawal are predictors of outcome. However, the presence of at least one, between titers of TRAb or their rate of fall at six months, resulted to be the best predictor of remission with the higher sensitivity and specificity.     

Double-Blind Study of Alprazolam, Diazepam, Clonidine, and Placebo in the Alcohol Withdrawal Syndrome: Preliminary Findings

Both a reduction in the inhibitory effects of GABA (disinhibition) and activation of the sympathetic nervous system are manifested during the alcohol withdrawal syndrome. This study was designed to explore the relative efficacy of medications that differentially affects these two biological systems: the benzodiazepines, which attenuate GABAergic disinhibition, and the α₂-adrenergic receptor agonists, which decrease sympathetic activation. The benzodiazepine diazepam ( n = 6), the α₂-receptor agonist clonidine ( n = 7), the benzodiazepine alprazolam (that is also purported to have α₂-receptor agonist properties) ( n = 6), and placebo ( n = 6) were evaluated in their effectiveness in decreasing signs and symptoms of alcohol withdrawal. Drug-free, alcohol-dependent patients were administered 1 of the 4 medications in a double-blind design until symptoms of withdrawal, as measured by the Clinical Instrument Withdrawal Assessment for Alcohol-Revised, were successfully treated. Alprazolam was significantly more efficacious than both clonidine and placebo in decreasing withdrawal symptoms. Diazepam was more effective than clonidine and placebo on some measures of withdrawal. Clonidine decreased systolic blood pressure significantly more than the other two active drugs and placebo, but was no more effective than placebo in decreasing other symptoms of withdrawal. Alprazolam did not significantly decrease blood pressure compared with diazepam or placebo. Despite the small sample size, these preliminary findings suggest that the efficacy of alprazolam in the treatment of alcohol withdrawal is related to its effect at the benzodiazepine receptor and not its α₂-receptor agonist properties.     

Prediction of relapse after antithyroid drug therapy of Graves' disease: value of color Doppler sonography.

Opinions differ regarding the indications for antithyroid drugs, radioiodine and surgery in patients with Graves' disease because the likelihood of long-term remission after medical treatment cannot be predicted. The aim of this study was to assess the value of quantifying thyroid blood flow in an attempt to predict outcome following withdrawal of antithyroid drug therapy. Spectral Doppler recordings were obtained from the thyroid arteries in 24 patients with Graves' disease at the time of diagnosis. Thyroid blood flow levels measured at the time of diagnosis of Graves' disease were correlated with outcome following withdrawal of medical treatment (mean duration of treatment: 14 months). Clinical follow-up for at least 18 months (range: 18 - 39 months) after antithyroid drug withdrawal was possible in 13 patients (12 women). Mean peak systolic velocity and volume flow rate values as well as thyroid volume measured at the time of diagnosis were significantly higher (139 cm/s, SD 46; 195 ml/min, SD 170; 52 ml, SD 18) in patients who relapsed after drug treatment compared with patients in remission (71 cm/s, SD 27; 67 ml/min, SD 61; 25 ml, SD 13). The correlation between thyroid blood flow measurements and thyroid volume was high (r = 0.79 - 0.96). Recurrence of disease could be predicted with a sensitivity of 71 % and a specificity of 100 % based on thyroid blood flow measurements. This preliminary data suggest that quantification of thyroid blood flow by means of Doppler sonography might be a useful tool to predict the outcome of Graves' disease following withdrawal of medical treatment and could be helpful in finding the adequate kind of therapy.     

Eating disorders and concurrent psychopathology: a reconceptualisation of clinical need through Rasch analysis

Therapies for anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED) and eating disorder not otherwise specified (EDNOS) take as their focus, perhaps of necessity, the eating disorder symptomatology. However, there is increasing evidence of comorbidity of psychopathological mechanisms (e.g. perfectionism, depression) with eating disorders which, left untreated, may diminish any therapeutic effects. Thus identifying the extent of comorbidity in an eating disorder population and assessing the relationship between psychopathological mechanisms and the eating disorder is important. Rasch analysis was applied to the findings from questionnaires (EDI‐2; SCL90‐R) completed by 105 female patients referred to an eating disorder unit. General psychopathology was found to be more indicative of ‘caseness’ than eating disorder psychopathology. In particular, interpersonal sensitivity, depression and mild interpersonal aspects of psychoticism emerged as important factors across eating disorders. The comorbidity of psychopathological mechanisms needs to be given consideration in the successful treatment of eating disorders. Copyright © 2007 John Wiley & Sons, Ltd and Eating Disorders Association.     

Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial

BACKGROUND: In alcohol withdrawal, fixed doses of benzodiazepine are generally recommended as a first-line pharmacologic approach. This study determines the benefits of an individualized treatment regimen on the quantity of benzodiazepine administered and the duration of its use during alcohol withdrawal treatment. METHODS: We conducted a prospective, randomized, double-blind, controlled trial including 117 consecutive patients with alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, entering an alcohol treatment program at both the Lausanne and Geneva university hospitals, Switzerland. Patients were randomized into 2 groups: (1) 56 were treated with oxazepam in response to the development of signs of alcohol withdrawal (symptom-triggered); and (2) 61 were treated with oxazepam every 6 hours with additional doses as needed (fixed-schedule). The administration of oxazepam in group 1 and additional oxazepam in group 2 was determined using a standardized measure of alcohol withdrawal. The main outcome measures were the total amount and duration of treatment with oxazepam, the incidence of complications, and the comfort level. RESULTS: A total of 22 patients (39%) in the symptom-triggered group were treated with oxazepam vs 100% in the fixed-schedule group (P<.001). The mean oxazepam dose administered in the symptom-triggered group was 37.5 mg compared with 231.4 mg in the fixed-schedule group (P<.001). The mean duration of oxazepam treatment was 20.0 hours in the symptom-triggered group vs 62.7 hours in the fixed-schedule group (P<.001). Withdrawal complications were limited to a single episode of seizures in the symptom-triggered group. There were no differences in the measures of comfort between the 2 groups. CONCLUSIONS: Symptom-triggered benzodiazepine treatment for alcohol withdrawal is safe, comfortable, and associated with a decrease in the quantity of medication and duration of treatment.