Malcolm Lader

• King's College London

Benzodiazepine: uso, abuso e dipendenza Dall'epidemiologia al trattamento 2013 VERONA EDIZIONI CLAD-ONLUS WWW.MEDICINADIPENDENZE.IT

The benzodiazepines (BZDs) are anxiolytics, hypnotics, anticonvulsants, muscle-relaxants and induce anaesthesia. Adverse effects comprise sedation subjectively and cognitive and psychomotor impairment objectively Complex skills such as driving can be compromised. Paradoxical excitement can have forensic implications. Long-term use beyond the licens...

To test whether satisfaction with taking medication, assessed using item 15 of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), is associated with clinical outcome and persistence with treatment. In this post hoc analysis, data were analyzed from 4 randomized placebo-controlled studies of patients with major depressive disord...

To re-examine various aspects of the benzodiazepines (BZDs), widely prescribed for 50 years, mainly to treat anxiety and insomnia. It is a descriptive review based on the Okey Lecture delivered at the Institute of Psychiatry, King's College London, in November 2010. A search of the literature was carried out in the Medline, Embase and Cochrane Coll...

Abstract Purpose. The use of benzodiazepines remains a source of controversy. Some prescribers believe that they are beneficial and espouse their use; others regard their risk:benefit ratio as too adverse for any but occasional use. This review considers these viewpoints based on the appropriate literature. Survey. The recent English-language liter...

The case of a man originally diagnosed as having a personality disorder is presented. Follow-up over many years revealed that he was really suffering from a bipolar manic-depressive disorder which responded well to lithium. His later life was characterized by stability.

1. Dependence to benzodiazepines is difficult to induce in animals but has been induced by high doses in man. Case reports of benzodiazepine dependence are rare compared with the usage of these drugs, but provide no proper epidemiological framework for the estimation of risk. Patients taking these drugs for four months or more may develop symptoms...

The use of benzodiazepine anxiolytics and hypnotics continues to excite controversy. Views differ from expert to expert and from country to country as to the extent of the problem, or even whether long-term benzodiazepine use actually constitutes a problem. The adverse effects of these drugs have been extensively documented and their effectiveness...

The topic of drug addiction or misuse of drugs has numerous far-reaching ramifications into areas such as neuroscience, medicine and therapeutics, toxicology, epidemiology, national and international economics and politics, and the law. The general principles of drug addiction are first summarised. A recurring and intrinsic problem is lack of adequ...

The diagnostic criteria for anxiety disorders have changed markedly over the past 50 years and continue to evolve. However, Professor Malcolm Lader, Emeritus Professor of Clinical Psychopharmacology, King's College London, argued in his Keynote Lecture at the Latest Advances in Psychiatry Symposium earlier in the year, that these changes might refl...

The benzodiazepines have been extensively prescribed for decades for vague indications such as anxiety, sleeplessness and muscle tension. Despite increasing knowledge of their adverse effects, such as sedation, psychomotor and cognitive impairment, and dependence on long-term use, and the recent advent of better alternatives, their use continues la...

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a...

Parkinson's disease is a common condition, usually treated by dopaminergic agents, both ergot and non-ergot. Many behavioural abnormalities are associated with such usage, including impulse control disorders (ICDs), dopamine dysregulation syndrome and 'punding'. Pathological gambling, a form of ICD, comprises persistent and maladaptive gambling of...

The proportion of diagnosed depressives prescribed antidepressants has increased markedly over the last 20 years, mainly following the introduction of the selective serotonin reuptake inhibitors. However, currently available antidepressants have notable limitations, relating to their only moderate efficacy relative to placebo, relatively slow onset...

Schizophrenia is a life-threatening disease associated with mortality rates that are two to three times higher than those expected/observed in the general population. It is associated with high levels of suicide, particularly in young male patients soon after diagnosis. Delays in treating schizophrenia could contribute to the high number of suicide...

A review of published evidence of superior efficacy of a particular antidepressant in major depressive disorder may assist clinicians in making considered treatment choices. To identify such candidates, an international group of experts met to assess published evidence (identified through searches in Medline and Embase databases and discussions wit...

The acceptability of antidepressants among both professionals and the lay public, including depressed patients, has been set back by insistent reports of an enhanced suicidal risk. This encompasses suicidal ideas, intention, attempts and completed acts. Such behaviour is an intrinsic feature of the more depressed individuals and it is difficult to...

The present overview investigates whether different antidepressants have differing discontinuation symptoms upon treatment cessation, if these symptoms vary between depression and anxiety disorders, and with length of treatment. Data came from two comparative studies of escitalopram in major depressive disorder (MDD) (one vs. venlafaxine XR and one...

Depression is the most frequent and costly problem in primary care, where most of these patients are seen and treated. In many countries, the public regard antidepressant drugs as 'addictive', partly because of the withdrawal symptoms that can occur when they are discontinued. Indeed, discontinuation (withdrawal) symptoms can follow the stoppage of...

The purpose of this article is to describe the current status of knowledge on excess mortality in schizophrenia and its causative factors, and to expand upon previous work evaluating approaches that may reduce mortality rates. Literature available since 1995 was identified in a computerized search of the bibliographical databases Medline and Embase...

A previous factor analysis of pooled data demonstrated that the Liebowitz Social Anxiety Scale (LSAS) can be divided into six subscales. This paper examines data from a fixed-dose trial of escitalopram versus paroxetine, in order to determine the differential effects of these agents on symptom dimensions in social anxiety disorder (SAD). Data from...

Benzodiazepine hypnotics are widely abused as pan of a polydrug misuse culture. This study set out to investigate some pharmacokinetic and pharmacodynamic characteristics of a novel method of abuse, snorting, of flunitrazepam. Twenty healthy volunteers took pan: three took 0.5 mg, three took I mg, three took l.5 mg, six took 2 mg and five took plac...

Alzheimer’s disease (AD) patients show a greater disruption of the circadian sleep-wake cycle as compared to similarly aged non-demented controls. When this occurs demented patients spend their nights in a state of frequent restlessness and their days in a state of frequent sleepiness. These sleep-wake disturbances became increasingly more marked w...

Fatigue, daytime sleepiness, and hypersomnia are commonly associated with affective illnesses. In major depressive disorder, they not only accompany the acute episode, but also frequently precede its onset. These symptoms also often complicate the recovery phase itself. In this chapter, the longitudinal course, manifestations, and treatment of slee...

The present article proposes a pharmacostrategy for the treatment of sleep and arousal disturbances in Parkinson’s disease (PD) patients. Among the factors that affect the quality of life in PD patients, sleep disturbances play a major role along with depression and inappropriate independence in daily activity. To apply this tharapeutic approach, t...

Today, a chronobiotic is defined as a substance capable of shifting the phase of the CTS and reentraining circadian rhythms that have been dissociated in the short-term, or desynchronized in the long-term. The most widely recognized chronobiotic is melatonin. Its phase-shifting effects have been studied extensively. Surprisingly, the synchronizing...

Our general conclusion is that the main function of REM sleep is the restoration of search activity in the subsequent wakefulness. In wakefulness search activity in a normal state is relevant to the reality, goal directed and task oriented and sustained by the interrelationships between brain activating and activity modulating brain monoamines. Ren...

Insomnia is a common feature in schizophrenia. The sleep disturbance of either never-medicated or previously treated schizophrenia patients is characterized by an increase of stage 2 sleep latency and wake time after sleep onset, and a reduction of total sleep time and sleep efficiency. In addition, stage 4 sleep, slow wave sleep, and REM latency a...

In conclusion, in rehabilitation of the ABI patient, not only must the patient overcome a number of cognitive, psychiatric and physical difficulties, but also sleep difficulties which are often difficult to treat. Notwithstanding, an attempt is certainly required as without it it is difficult to provide a better psychosocial outcome for these patie...

Study Objectives Visual analog scales (VAS) and diary cards are used to measure changes in patients’ sleep quality in clinical trials and practice. In this study we compared the 2 methods for assessing changes in sleep quality in patients with insomnia. Methods A VAS method of assessing sleep quality (QOS-means of questions 4 and 5 in the Leeds Sle...

Chronic primary insomnia is a recurrent condition that negatively effects the daily functioning of patients diminishing the quality of their lives. It is associated with and in some situations is a risk factor in both psychiatric (depression) and physical illness (cardio-vascular). Treatment effectiveness in insomnia has been shown short term for b...

Drugs, such as sedative-hypnotics and anesthetics, are able to strongly regulate the vigilance state by affecting the main fast inhibitory neurotransmitter receptor system in the brain, the GABAA receptor system. Agonists, such as classical benzodiazepines, are today the most widely used hypnotics. This review summarizes the recent molecular and be...

Benzodiazepines are commonly used to provide sedation for infants and children undergoing intensive care or diagnostic and therapeutic procedures in a variety of clinical settings. This chapter focuses on Midazolam as representative of this class of drug. Midazolam provides sedation by altering the neuroinhibitory pathway mediated by gamma-aminobut...

The typical behavioral characteristics of the night eating syndrome have been described as morning anorexia, evening hyperphagia and insomnia. The neuroendocrine characteristics have been described as changes in the circadian rhythm by an attenuation in the nocturnal rise of the plasma concentrations of melatonin and leptin and an increased circadi...

This chapter details the pattern of sleep disturbances associated with chronic medical conditions. It illustrates the disturbances in sleep architecture manifested by a number of medical conditions as detailed by EEG or polysomnography. Sleep disturbances are common with a number of medical conditions and abnormal health states may also lead to pri...

Among the proposed functions of dreaming in human being, the most research supports are mood-regulation, problem-solving, learning, and memory construction. Recent imaging techniques have provided meaningful information on functional neuroanatomy and neurophysiology of REM sleep and dreaming. In addition to serotonin, norepinephrine, and acetylchol...

Insomnia is a common complaint encountered in general practice which causes considerable distress to the sufferer. These patients present both a diagnostic and management challenge for primary care physicians. Despite the frequency with which the disorder is encountered most doctors consider themselves lacking in both knowledge and expertise indica...

Rapid eye movement sleep is a unique paradoxical state within sleep period. Normally it follows deep sleep, is maintained for varying duration and may terminate in either sleep or wake state. During REM sleep some neurons increase firing, the REM-ON neurons, while some others cease firing, the REM-OFF neurons. Although the mechanism is not complete...

The major hormone of the circadian system, melatonin, plays an important role in human sleep regulation, acting via both circadian and homeostatic mechanisms. Melatonin treatment can be used to treat chronic insomnias of different origin and circadian sleep disorders. However, if administered in high doses or at inappropriate times, melatonin might...

The high prevalence of sleep disturbance in chronic pain conditions is due in part to bi-directional influences in which pain disturbs sleep and poor sleep reduces pain thresholds and aggravates pain. Other variables, especially depression and anxiety, may mediate this relationship, although supporting data has been equivocal. Trauma exposure and r...

The current first-line treatment for patients with winter seasonal affective disorder (SAD) is bright-light therapy, that is exposure to strong artificial light visible to the eye. Patients at risk of light-induced eye damage, such as those using photosensitizing medication, need to consult an ophthalmologist before the bright-light therapy is star...

The mechanisms by which both natural sleep and anesthesia generate and maintain a loss of consciousness are currently the focus of much investigation. The neuronal networks of substrates mediating endogenous regulation of consciousness level are complex. Much research has focused on understanding the neural correlates of wakefulness, NREM sleep, RE...

Psychological (e.g., stress), physiological (e.g., pregnancy), pharmacological (e.g., caffeine and SSRIs) and pathological (e.g., renal failure and Parkinson’s disease) factors all play a role in RLS and PLMD. Sleep specialists debate whether continuous long-term treatment for an undulating (but at times very disruptive condition) is merited. In “q...

Benzodiazepines (BZDs) constitute the most widely used symptomatic treatment of insomnia and anxiety. Many of these drugs are associated with adverse effects, such as daytime sedation and dependence with continued use. There is a concern about the rationale for and extent of benzodiazepine (BZD) use. There is a general awareness that BZD use is ina...

Besides the obstructive sleep apnea/hypopnea syndrome, the most prevalent cause of hypersomnia, other disorders may be the cause of more severe hypersomnia. These include primary disorders of the central nervous system and hypersomnia associated with various medical disorders. Among the first ones are narcolepsy-cataplexy, idiopathic hypersomnia an...

It is intuitive that CNS-active drugs have the potential to affect perceptual and psychomotor skills relevant to driving. Yet, variability in testing paradigms and difficulty in controlling performance-testing conditions continue to create challenges in achieving a more exact understanding of pharmacological influences on driving behavior. Advances...

SSRIs have marked dose-dependent effects on REM sleep in healthy volunteers and depressed patients, with REM onset latency being lengthened and REM amount being reduced. After weeks of treatment REM latency remains long, but the amount of REM recovers, and shows rebound after withdrawal. These changes in amount of REM sleep may reflect receptor ada...

The importance of timing medications is noted in the context of the effects of psychotropic drugs. The information here assembled as yet is examined mostly by inspection with the unaided eye and conventional (rather than time series-related) statistics. An effect of time, shown by an analysis of variance, however, awaits an inferential statistical...

Poor sleep quality often results in decreased alertness, drowsiness and sleepiness the following day. Pharmacological treatment of sleep complaints can aggravate these effects, resulting in impaired performance at work and during daily activities such as driving a car. The first hypnotics, the barbiturates, have a limited safety profile and produce...

The study of the neuropharmacology of dreaming and nightmares is an area of neuroscience in its infancy. Dreaming and nightmares are an area of study replete with grand theories and a paucity of actual data. Evidence from neuropathology studies, generalized CNS drug effects and side effects, electro physiology and CNS neuroimaging studies is beginn...

There are several herbs that have central depressant effects and have been used for anxiolytic and sedative effects historically. This has been supported by neuropharmacological, animal, and human studies. Kava, valerian, and passionflower have been the best supported by research in this regard, although others show potential. Much work remains to...

Hypnotic drugs are consumed mainly by chronic users, who often take hypnotics for years continuously. Two studies of the American Cancer Society, each involving over 1 million subjects followed prospectively for 6 years, showed that hypnotic use predicted increased mortality after control for comorbidities. At least 8 other studies have also noted...

Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from...

The results from three 8‐week escitalopram studies in major depressive disorder are presented with respect to efficacy and the effect on sleep quality, both in the full population and the subpopulation of patients with sleep problems at baseline. Analysis of pooled data from these randomized, double‐blind, placebo‐controlled, studies in which cital...

Selective serotonin reuptake inhibitors are the first-line treatment for panic disorder. They are effective and well tolerated. Although tricyclic antidepressants are equally effective, they are less well tolerated than the selective serotonin reuptake inhibitors. Monoamine oxidase inhibitors can be efficacious but have a range of unwanted effects...

Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from...

Selective serotonin reuptake inhibitors are the pharmacological treatment of choice for the treatment of social anxiety disorder (SAD). The efficacy and tolerability of fixed doses of escitalopram were compared to those of placebo in the long-term treatment of generalised SAD, using paroxetine as an active reference. Patients with a DSM-IV diagnosi...

We evaluated the relative efficacy of venlafaxine XR on the psychic versus somatic symptoms of anxiety in patients with generalized anxiety disorder as determined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Data were pooled and analyzed from 1,841 patients with generalized anxiety disorder who participated in five sho...

Escitalopram has demonstrated efficacy for the acute treatment of social anxiety disorder (SAD) in two placebo-controlled trials and for long-term treatment in a relapse-prevention study. Social anxiety disorder is a heterogeneous disorder. This study questions whether this new selective serotonin reuptake inhibitor is effective across different su...

To review clinical information on the incidence and causes of hyponatremia (defined as a serum sodium level <130 mEq/L), the most common electrolyte abnormality seen in general hospital patients, and to discuss the diagnosis and treatment of hyponatremia in relation to these factors. Primary sources and review articles were identified via MEDLINE (...

IntroductionSleep HygieneRelaxation and Non-pharmacological TechniquesHypnotic DrugsBenzodiazepine HypnoticsLong-acting CompoundsIntermediate-acting CompoundsShort-acting CompoundsUnwanted EffectsOverviewBenzodiazepine-like Hypnotics ZopicloneZolpidemZaleplonImplications of Subtype-selective Benzodiazepine Receptor Ligand HypnoticsCompounds Used as...

Tianeptine (37.5 mg/day) and paroxetine (20 mg/day) were compared in a population of depressive patients without past or current history of co-morbid anxiety and/or important anxiolytic treatment. In a 6-week, double blind trial, the special focus was on anxious symptoms. Both drugs showed good efficacy on depressive symptomatology, assessed with M...

Benzodiazepines have major drawbacks including lessening of anxiolytic effect in long-term use, impairment of psychological functioning, problems on discontinuation, and addiction potential. Alternatives have been sought including the antihistamines such as hydroxyzine. Two studies are described, one comparing hydroxyzine 50 mg/day with placebo in...

Brain uptake of 123I-iomazenil was studied in seven cirrhotic patients and eight normal controls using single photon emission computerized tomography. The highest concentration of the ligand was found in the occipital cortex, which corresponds to the brain region with the highest concentration of benzodiazepine receptors. The peak uptake was delaye...

Patients suffering from major depression (DSM-IIIR) with a baseline Hamilton Depression Rating Scale of 18 or more were recruited in ten general practices. They were allocated randomly to treatment with either lofepramine (n = 52) or dothiepin (n = 54). Of the total, 60 were female; their mean age was in the early 40s. The drugs were administered f...

Both published and unpublished data concerning the rebound, withdrawal, dependence and abuse potential of zopiclone have been reviewed. As expected for an hypnotic drug of about 5 h elimination half-life, rebound has occasionally been detected but is substantially less frequent than with equivalent benzodiazepines. Tolerance to zopiclone does not o...

Scopolamine (SP) and lorazepam have different pharmacological actions but exert very similar effects on people's performance on a wide range of cognitive and psychomotor tasks. Recent research suggests that their effects may be dissociable on perceptual priming. The present study compared the acute effects of SP (0.3 and 0.6 mg sc), lorazepam (1.0...

At doses greater than 125–150 mg daily, tricyclic antidepressants (TCAs) have been shown to be effective in patients with depressive illness. There is nevertheless, a pronounced tendency in general practice to prescribe antidepressants at half the dose likely to be prescribed for the same patient by a psychiatrist. The principal motivation for subt...

Forty normal subjects (mean age 36) had their caffeine intake estimated by keeping a diary (n=40) and also by analysing provided samples of tea and coffee (n=28). A test dose of caffeine (500 mg) was given and a series of salivary samples analysed to estimate pharmacokinetic measures of the rate of caffeine metabolism. They then underwent 48 h of p...

The effects of lorazepam (1,2 mg) and placebo on encoding, remembering and awareness were assessed in a study with 54 healthy volunteers. All subjects studied stimulus materials in a levels of processing (L-o-p) task. Half the subjects were assessed on an explicit memory task of word recognition and the other half were given an implicit memory task...

Ligands to the benzodiazepine receptor (BZR) accumulate in hepatic encephalopathy; the benzodiazepine antagonist flumazenil can reverse some manifestations of this condition. This study was designed to explore the effects of flumazenil on cognitive function and anxiety levels in cirrhotic patients without hepatic encephalopathy. Twenty such patient...

Twenty four long-term benzodiazepine users were allocated randomly to treatment with either buspirone (mean dose 25 mg/day) or placebo, prior to tapering off the benzodiazepine over 6 weeks. In both groups, six out of 12 patients successfully completed withdrawal. However, buspirone-treated patients tended to have lower anxiety levels than placebo-...

Biochemical and psychophysiological effects of augmenting serotonergic and noradrenergic function were compared in 12 normal volunteers. Fluvoxamine (100 mg), a serotonin (5-HT) re-uptake inhibitor, maprotiline (75 mg), a noradrenaline re-uptake inhibitor, and placebo were given for 7 days each to each subject. Subjects were tested pre-drug on days...

Synopsis Benzodiazepines (BZs) produce transient anterograde amnesia when given to normal subjects. The present longitudinal study assessed whether BZs impair memory functions in a clinically anxious group. Eighty-two agoraphobics with panic disorder were randomly allocated to one of four treatment groups resulting from a combination of two drug tr...

Benzodiazepine hypnotics are widely abused as part of a polydrug misuse culture. This study set out to investigate some pharmacokinetic and pharmacodynamic characteristics of a novel method of abuse, snorting, of flunitrazepam. Twenty healthy volunteers took part: three took 0.5 mg, three took 1 mg, three took 1.5 mg, six took 2 mg and five took pl...

The anxiety disorders are common conditions - community surveys suggesting that at any one time about 3-5% of the adult population suffers generalised anxiety or panic disorder. However, many more suffer lesser degrees of anxiety, usually related to stresses in the environment, so that at least 15% of patients attending general practitioners' surge...

The concepts of dependence, addiction and abuse comprise overlapping clinical phenomena. The earlier anxiolytic drugs, in particular the barbiturates, were prone to abuse, i.e., non-medical use, and to high-dose misuse. Their modern counterparts, the benzodiazepines, are abused in a patchy way and are sometimes taken in regularly high doses. Howeve...