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Behavioural Toxicity of Medicinal Drugs
Abstract
Behavioural toxicity is relatively common among medicinal drug users and evidence shows that drugs frequently produce adverse effects that prevent their users from performing everyday operations in a normal manner. Epidemiological research generally indicates that the use of sedative drugs is associated with an increased risk of becoming involved in injurious accidents. Empirical studies have also demonstrated adverse effects of sedative drugs on the performance of healthy volunteers and patients in laboratory tests designed to measure psycho-motor and cognitive function, and in real life-tests measuring on-the-road driving performance. Empirical studies also indicate that behavioural toxicity can vary widely between individual drugs depending on differences in dose, dosing regimen, duration of treatment, pharmacokinetics or mechanisms of actions. Besides sedation, other CNS adverse effects such as aggression, paranoia, social withdrawal or lack of motivation may disrupt or prevent the initiation of normal performance, thus imposing a burden on the ability of the patients to function in a normal manner. Emotional disturbances are rare as indicated by the small number of case reports that mention their existence. Yet theses disturbances sometimes involve severe reactions that are more debilitating than sedation. Behavioural toxicity can be minimised by avoidance of pharmacodynamic and pharmacokinetic drug interactions, adjustment of dosage regimens to a patient’s individual response to a drug, nocturnal administration of drugs that are expected to produce sedation and patient education on the potential risks of the drugs they receive. Much of this information can be gained from experimental literature comparing the effect of individual drugs on performance. Unfortunately this is presently incomplete, since most research on behavioural toxicity has been confined to psychiatric drugs. Yet, in the interest of the patient, it should be the responsibility of drug manufacturers and regulators to always identify problematic drugs.
... The primary outcome measure of the driving test is standard deviation of lateral position (SDLP) (O'Hanlon 1984). This standardized driving test has been applied in over 75 studies and demonstrated sensitivity to the impairing effects of several central nervous system (CNS) drugs (Brookhuis et al. 1990;Ramaekers 1998Ramaekers , 2003Theunissen et al. 2014;Vermeeren 2004;Vermeeren et al. 2009;Verster et al. 2004). ...
Introduction:
The on-the-road highway driving test is generally regarded as a gold standard for assessing drug-induced driving impairment. The primary outcome measure is the standard deviation of lateral position (SDLP), a measure of road tracking error or "weaving". The test has been calibrated for incremental doses of alcohol almost 30 years ago in order to define the impact of drug-induced impairment in terms of blood alcohol concentration (BAC) equivalents. Drug-induced changes in SDLP exceeding 2.4 cm have been evaluated as clinically relevant ever since. The present analysis was conducted to assess the robustness of the alcohol effect in a range of on-the-road driving studies which have been conducted since the initial alcohol calibration study.
Methods:
The present study pooled data of 182 participants from nine placebo-controlled crossover studies who performed the highway driving test, while their BAC was at or just below the legal limit for drivers (i.e., 0.5 g/L).
Results:
Overall, mean SDLP increased with 2.5 cm (95% CI 2.0-2.9 cm). Equivalence testing showed that the clinical relevance criterion value of 2.4 cm fell well within the 95% CI in each individual study. Gender did not affect alcohol-induced changes in SDLP.
Discussion:
These results demonstrate the robustness and validity of the clinical relevance criterion for SDLP as measured during on-the-road driving.
... Furthermore, it is important to notice that the memory effects of paroxetine persisted throughout the treatment period. This is consistent with the notion that, while the sedating effects of histaminergic or noradrenergic blockade are most pronounced following acute administration and diminish over time due to tolerance, the direct effects of anticholinergic actions on memory performance are resistant to tolerance and may occur as long as the treatment continues (Thompson, 1991;Ramaekers, 1998). ...
The current study was carried out to investigate the cognitive effects of two serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, with special reference to differences in their affinity for other neurotransmitter systems, i.e. anticholinergic activity of paroxetine and putative dopamine reuptake activity of sertraline. The study was conducted according to a double-blind, three-way cross-over design. During three treatment periods of 2 weeks, 24 healthy middle-aged (aged 30-50 years) subjects of both sexes received sertraline (50 mg on days 1-7, 100 mg on days 8-14), paroxetine (20 mg on days 1-7, 40 mg on days 8-14) and placebo. Paroxetine specifically impaired delayed recall in a word learning test at a dose of 20 and 40 mg. Sertraline did not affect word learning but improved performance on a verbal fluency task at a dose of 50 and 100 mg. Neither drug affected performance on a short-term memory scanning task. These subtle but significant changes in cognitive performance can be explained by subtle differences in pharmacological profiles of these SSRIs. The additional anticholinergic effects of paroxetine could account for its induction of long-term memory impairment. Similarly, the additional dopaminergic effects of sertraline could account for its induction of slightly improved verbal fluency. The impairing and facilitating cognitive effects of paroxetine and sertraline, respectively, may be more pronounced in the elderly depressed patient.
Neuroleptic (antipsychotic) drugs affect the individual more like a viral brain disease called lethargic encephalitis than like any medical treatment. The neuroleptic pioneers saw how these drugs caused emotional indifference, disinterest, and apathy similar to lethargic encephalitis. They realized the drugs also produced neurological syndromes similar to those associated with the epidemic encephalitis, including Parkinsonism and tardive dyskinesia (TD). They predicted the new drugs could cause an epidemic of brain injury similar to the viral encephalitis. Given the severe adverse reactions TD can produce, even if the drugs brought enormous benefit, the cost would be too high. Yet the drugs have no curative value whatsoever and can only work by imposing encephalitis-like lethargy, disinterest, and apathy upon individuals, making them seemingly less troublesome to themselves and others. It is time to reconsider their use.
In order to identify the major risk factors for crashes in the area of the Province of Parma, North Italy, Police Reports of 1,489 road accidents occurring in 2008 were analysed. Logistic regression was used to evaluate the association between driver and accident characteristics with accident severity. Age groups most involved in road crashes were 26-35 year olds and 36-45 year olds. Women were less frequently involved in accidents than men. The hourly distribution of accidents for working days, Saturdays and Sundays showed that the main differences were evident late at night (12 a.m.-3 a.m. on Sunday and 4-7 a.m. on Saturday, respectively). The youngest age group was involved in a greater number of accidents, which greatly increased between 12 a.m.-3 a.m. As for the causes of road crashes, about half of them were attributed to violations, while speeding was found to be the second most frequent road crash cause, surpassing alcohol and drug abuse. The risk of involvement in severe rather than non-severe accidents was significantly related to vehicle type, in that motorcycle drivers suffered more serious injuries in comparison to car or lorry drivers. These data should influence local transport safety measures and policies.
Lorazepam, a benzodiazepine anxiolytic, may increase daytime sleepiness and impair psychomotor performance, which is hazardous for patients engaging in daily activities such as car driving. Given current prescription practice, information on the repeated dose effects is required. The 5-HT2A/2C antagonist ritanserin was originally developed as a safer alternative to the benzodiazepines, yet having limited clinical efficacy. 5HT2A/2C receptors have been implicated in regulating slow-wave sleep but little is known about their role in human performance.
The present study investigated the subchronic effects of the benzodiazepine anxiolytic lorazepam and the 5-HT2A/2C antagonist ritanserin on actual driving performance, objective and subjective sleepiness, and nocturnal slow wave sleep.
Eighteen healthy volunteers were treated twice daily for 7 days with ritanserin 5 mg, lorazepam 1.5 mg or placebo. Treatments were administered according to a double-blind, cross-over design. Tests were performed on day 7 of each treatment week. Sleep EEG was recorded during the preceding night.
Lorazepam had a pronounced impairing effect on lateral position control and induced daytime sleepiness, while having no effect on other parameters. In contrast, ritanserin did not impair driving performance or affect objectively measured daytime sleepiness, while subjects reported to feel more alert during daytime. Moreover, consistent with its effects on 5-HT2 receptors, ritanserin increased the amount of nocturnal slow wave sleep. There were no relationships between changes in slow wave sleep and performance parameters.
Lorazepam administered for 7 consecutive days may be hazardous for patients who engage in driving activities. Antagonism of 5-HT2A/2C receptors, as accomplished by ritanserin, increases slow wave sleep and is devoid of effects on objective sleepiness and driving behaviour. Whether this extends to other cognitive and psychomotor domains remains to be established.
riving a motor vehicle is a complex task requiring a reasonable level of physical fitness, accurate perception, and appropriate
judgment. All these factors can be affected by drugs and alcohol, greatly increasing the risk of accidents. Many medical conditions
(and their treatments) may impair fitness to drive and are considered first.
There has been increasing concern regarding the role of prescription drug use in the causation of traffic crashes. The goal of this research is to describe the prevalence of prescription drug use among injured trauma patients and determine the association between classes of drugs and crash culpability, a surrogate measure of crash risk.
Patient records, including chronic medication usage, for all drivers admitted to a trauma center following a traffic collision in 2008 (N=1,558) were linked with police crash reports to determine crash culpability. Multivariable analyses explored the association between medication use and crash culpability among non-drinking drivers. Adjusted odds ratios and 95% confidence intervals were compared among drivers who were and were not using central nervous system (CNS)-acting medications (single and multiple).
61.5% of all drivers were using any medications and usage increased with age, as did numbers of prescriptions per driver. Logistic regression analyses revealed that drivers who used CNS medications had an increased risk of culpability; those on more than one such medication had a crude (unadjusted) odds ratio of 2.16 for having caused the crash. Among drivers less than 45 years old, CNS medications did not significantly increase the risk of crash culpability. However, among drivers aged 45 or greater, the odds ratios for one, two, or 2+ CNS medications vs. none increased dramatically from 1.89 to 4.23 to 7.99, respectively.
These results suggest that special attention should be given to older drivers (45+) using two or more CNS-acting agents.
In party circuits dexamphetamine is frequently used in combination with alcohol. It is hypothesized that co-administration of dexamphetamine to alcohol might reduce the sedative effects of alcohol, but may potentiate risk-taking behaviour.
The study was aimed at assessing the effects of alcohol, dexamphetamine and the combination of both on simulated driving and cognitive performance.
Eighteen subjects participated in a randomized, crossover, placebo-controlled study employing four conditions: 10 mg dexamphetamine, 0.8 g/kg alcohol, 10 mg dexamphetamine + 0.8 g/kg alcohol, and placebo. Fundamental driving skills and risk-taking behaviour were assessed in a driving simulator. Subjects also completed vigilance and divided attention tasks, and subjective ratings.
Mean BAC levels during simulated driving were between 0.91‰ and 0.64‰. Subjects using alcohol showed a significantly larger mean standard deviation of lateral position and shorter accepted gap time and distance. Use of alcohol or dexamphetamine + alcohol was associated with a higher frequency of red light running and collisions than the dexamphetamine or placebo conditions. Performance of vigilance and divided attention tasks was significantly impaired in the alcohol condition and, to a lesser degree, in the dexamphetamine + alcohol condition.
Single doses of 0.8 g/kg alcohol increased risk-taking behaviours and impaired tracking, attention and reaction time during a 3-h period after drinking when BACs declined from 0.9 to 0.2 mg/ml. The stimulatory effects of co-administration of dexamphetamine 10 mg were not sufficient to overcome the impairing effects of alcohol on skills related to driving.
The purpose of this study was to examine the association between psychoactive drug use and motor vehicle crash (MVC) injuries requiring hospitalization in southern Taiwan. A case-control study was conducted in southern Taiwan from January 2009 to December 2009. The cases included car or van drivers who were involved in MVCs and required hospitalization. Demographic and trauma-related data were collected from questionnaires and hospital and ambulance records. Urine and/or blood samples were collected on admission. The controls consisted of drivers who were randomly recruited while driving on public roads. Study subjects were interviewed and asked to provide urine samples. All blood and urine samples were tested for alcohol and a number of other legal and illegal drugs. Only those subjects who provided urine and/or blood specimens were included in the study. During the study period, 254 case patients and 254 control drivers were enrolled. The analysis showed an odds ratio (OR) of 3.41 (95% confidence intervals (95% CI), 1.76-6.70; p < 0.001) for persons taking benzodiazepines, and an OR of 3.50 (95% CI, 1.81-6.85; p < 0.001) for those taking alcohol (blood alcohol concentrations (BAC) ≥ 0.8 g/l) with regard to hospitalizations due to MVCs. For persons taking combinations of benzodiazepines and alcohol, the OR increased to 5.12 (95% CI: 1.77-15.91, p < 0.001). This study concluded that drug use among motor vehicle drivers increases the risk of MVCs that require hospitalization. From a public health perspective, the high risk ratios are concerning, and preventive measures are warranted.
The objective of this study was to determine the relationship between alcohol use, psychoactive drug use and road traffic injury (RTI). A case-control study was conducted among drivers in Bangkok, Thailand. Two hundred cases and 849 controls were enrolled between February and November 2006. Cases who sustained a RTI were matched with four controls recruited from petrol stations within a 1-km radius of the reported crash site of the case. A positive alcohol breath test (> or =50mg/dl), and positive tests for the presence of illicit (amphetamine, cocaine, marijuana) and non-illicit psychoactive drugs (antihistamine, benzodiazepine, antidepressants), using gas chromatography/mass spectrometry (GC/MS) were documented as primary measures. There were significantly higher odds of an alcohol breath test > or =50mg/dl (adjusted odds ratio (OR) 63.6 (95% CI: 25.5-158.9)), illicit psychoactive drugs (adjusted OR 3.4 (95% CI: 1.7-6.6)) and non-illicit psychoactive drug (adjusted OR 3.1 (95% CI: 1.5-6.3)) among cases than controls. Even though driving under the influence of psychoactive drugs has been significantly linked to RTI, its contribution to road safety is much lower than driving under the influence of alcohol. With limited resources, the priority for RTI prevention should be given to control of driving under the influence of alcohol.
Road injuries are the leading injury-related cause of death among people aged 15-44. A clear dose-effect relationship has been demonstrated for drug and alcohol use and road traffic accidents. The objective of our study was to estimate the prevalence of drug and/or alcohol use in subjects admitted for road traffic accidents to an Emergency Department.
In this study, conducted between January and April 2006, 100 patients of both sexes (age 18-65) examined after road traffic accidents were consecutively enrolled. A commercial rapid urine test was used to detect drugs by the Emergency Department staff The alcohol concentration was determined from a blood sample at the central laboratory.
Most of the patients were drivers under 35 years of age. 67/100 road traffic accidents occurred at the weekend (Friday-Sunday), nearly 60% between 24:00-09:00 hrs; on non-weekend days about 80% of road traffic accidents were recorded between 14:00-24:00 hrs (p < 0.0001). With the alcoholemia test and urine test for drugs detection 43/100 patients showed a single or multiple positivity. Alcohol and drug presence is relevant during the weekend (37/43 cases), in contrast with non weekend (6/43 cases) [OR 3.04 (95% CI 1.43; 6.46)]. Alcohol was the most frequently detected abuse substance (72%), followed by benzodiazepines (42%), tetrahydrocannabinol (21%) and cocaine (14%).
43% of patients examined were under the influence of psychotropic substances (alcohol, drugs or both). The greater part of road traffic accidents in positive test patients occurred during the week-end, in particular during the late night/early morning hours, probably after recreational time. The high incidence of alcohol and/or drug abuse may have caused physical and/or psychological problems, therefore the high number of road traffic accidents, especially if taken in combination.
The rapid urine test used cannot represent a diagnosis, and requires a confirmation test. It can be used for medical purposes as an easy and fast preliminary response which enables a faster diagnostic and therapeutic guideline, but it cannot be used for sanctions. Further studies are advisable with an increase of number of patients, in a wider temporal range, including control subjects, and using confirmation tests.
Many common pharmacological treatments have effects on cognitive ability. Psychometric task batteries used to characterize such effects do not provide direct information about treatment-related changes in brain function. Since overt task performance reflects motivation and effort as well as ability, behavioral measures alone may overestimate or underestimate the impact of a pharmacological intervention on brain function. Here we present a method that combines behavioral and neurophysiological measures in an attempt to detect the psychoactive effects of pharmacological treatments with greater sensitivity than that provided by behavioral measures alone. Initial application of the method is made to the data from a double blind, placebo-controlled, crossover study in which caffeine, diphenhydramine, and alcohol were used to alter the mental state of 16 healthy subjects at rest and while they performed low load and high load versions of a working memory task. For each intervention, more sensitive detection of drug or alcohol effects over a four hour period was obtained when EEG variables were included in multivariate analyses than when only behavioral variables were used. These initial results suggest that it can be useful to incorporate neurophysiological measures of brain activity into inferences concerning the acute impact of drugs on mental function, and demonstrate the feasibility of using multivariate combinations of behavioral and neurophysiological measures to sensitively characterize the pharmacodynamics of drug-induced changes in cognition.
Antidepressants may vary widely in their potential to impair cognitive and psychomotor functions. Little is known about their effects on event-related brain potentials (ERPs).OBJECTIVES. To compare the effects of three pharmacologically different antidepressants on performance and ERPs in tasks of selective attention and working memory.
Subjects were treated for 8 days with amitriptyline (sedative/anticholinergic TCA), nefazodone (5-HT(2) receptor antagonist), paroxetine (SSRI) and placebo, in a double-blind, crossover design. Measurements were carried out on day 1 and 8 of each treatment period. A task was used in which memory load (two and four items) and attention (focused, divided) were orthogonally varied.
On day 1 amitriptyline increased reaction times (focused attention) and the percentage of misses (load 4>load 2) and false alarms. Sensitivity (A') was reduced as a function of memory load. Effects were greatly diminished on day 8. The ERP analysis yielded a reduced early frontal positive difference wave related to memory load (day 1). Attention-related search negativity was slightly prolonged. P3 latency (stimulus evaluation time) was prolonged. P3 amplitude was reduced (mainly on day 8) suggesting diminished attention capacity. Nefazodone increased reaction times and miss rates and reduced sensitivity (A') on day 8 only. Paroxetine speeded responses on day 1 and slightly increased miss rates on day 8. Performance effects of nefazodone and paroxetine did not interact with the task factors. Search negativity and P3 measures were not affected.
The results suggest that the pharmacologically selective serotonergic antidepressants lack the specific memory and attention deficits seen with amitriptyline. Both performance and ERP data suggest that paroxetine and nefazodone may influence response-related processes, while for nefazodone an effect on other processes cannot be excluded.
Diphenhydramine may be associated with excess risk of injury relative to nonsedating H1-receptor antagonists.
This study sought to compare the risk of injury in patients exposed to diphenhydramine with the risk of injury in patients exposed to loratadine.
A retrospective cohort study of injury was carried out in 12,106 patients whose initial antihistamine prescription was for diphenhydramine and in 24,968 patients whose initial antihistamine prescription was for loratadine. Data were taken from a health care claims database that included employees, dependents, and retirees who filed claims from January 1991 through December 1998. Rates of six serious injuries in the diphenhydramine cohort after and before the first prescription were compared with rates in the loratadine cohort after and before the first prescription.
In the 30 days after the first antihistamine prescription, the rate of all injuries was 308 per 1,000 person-years in the diphenhydramine cohort versus 137 per 1,000 person-years in the loratadine cohort. The rate ratio estimate adjusted for age and gender using Poisson regression was 2.27 (95% confidence limits [CL] 1.93, 2.66). In the corresponding 30 days of the preceding year, the injury rates in the diphenhydramine and loratadine cohorts were 128 and 125 per 1,000 person-years, and the adjusted rate ratio was 1.02 (CL 0.83, 1.26). Thus, the cohorts appeared to have similar preprescription injury rates. The differences between the cohorts declined with time from prescription: For all injuries, the estimated percentage decline in the rate ratio was 4.1% per day (CL 3.3, 4.9), and the estimated time from the initial prescription until the diphenhydramine cohort returned to baseline risk was 32.3 days (CL 26.9, 37.6).
If these associations are causal, the percentage of the injuries attributable to diphenhydramine was 55% (CL 41, 65), implying a substantial number of excess injuries and costs incurred as the result of diphenhydramine use. The high use rates of this drug and the high incidence of injury suggest that further study of the association between injury and type of antihistamine is needed.
The current review summarizes the major results from all published studies from 1983 to 2000 (9 double-blind, crossover, placebo-controlled studies in healthy volunteers and 1 double-blind, baseline-controlled study in patients) that have determined the effects of antidepressants on actual driving performance using a standard test. That test measures driving impairment from vehicular "weaving" (i.e., standard deviation of lateral position [SDLP]) during 1 hour of on-the-road driving in normal traffic.
Changes in SDLP after acute doses of sedating antidepressants (i.e., amitriptyline, imipramine, doxepin, and mianserin) were comparable to those seen in drivers conducting the same test with a blood alcohol concentration of 0.8 mg/mL or more. Driving performance of subjects returned to placebo levels after 1 week of treatment, except after treatment with mianserin, for which the impairing effect lasted unabated over treatment. Nocturnal doses of sedating antidepressants (i.e., dothiepin, mianserin, and mirtazapine), however, did not produce residual driving impairment when measured the next day. Nonsedating antidepressants (i.e., moclobemide, fluoxetine, paroxetine, venlafaxine, and nefazodone) generally did not affect SDLP. However, SDLP rose to unacceptable levels after administration of combinations of nonsedating antidepressants and benzodiazepines with incompatible pharmacokinetic profiles. Correlational analyses demonstrated that conventional tests of psychomotor performance or self-ratings of side effects did not strongly predict antidepressant effects on SDLP. Regression analysis revealed a strong linear relation between antidepressant effects in the standard driving test and the number of patients reporting somnolence in clinical trials with the same antidepressants.
Application of actual driving tests remains essential to conclusively defining the potential hazard of drugs for driving.
The driving performance is easily impaired as a consequence of the use of alcohol and/or licit and illicit drugs. However, the role of drugs other than alcohol in motor vehicle accidents has not been well established. The objective of this study was to estimate the association between psychoactive drug use and motor vehicle accidents requiring hospitalisation. A prospective observational case-control study was conducted in the Tilburg region of The Netherlands from May 2000 to August 2001. Cases were car or van drivers involved in road crashes needing hospitalisation. Demographic and trauma related data was collected from hospital and ambulance records. Urine and/or blood samples were collected on admission. Controls were drivers recruited at random while driving on public roads. Sampling was conducted by researchers, in close collaboration with the Tilburg police, covering different days of the week and times of the day. Respondents were interviewed and asked for a urine sample. If no urine sample could be collected, a blood sample was requested. All blood and urine samples were tested for alcohol and a number of licit and illicit drugs. The main outcome measures were odds ratios (OR) for injury crash associated with single or multiple use of several drugs by drivers. The risk for road trauma was increased for single use of benzodiazepines (adjusted OR 5.1 (95% Cl: 1.8-14.0)) and alcohol (blood alcohol concentrations of 0.50-0.79 g/l, adjusted OR 5.5 (95% Cl: 1.3-23.2) and >or=0.8 g/l, adjusted OR 15.5 (95% Cl: 7.1-33.9)). High relative risks were estimated for drivers using combinations of drugs (adjusted OR 6.1 (95% Cl: 2.6-14.1)) and those using a combination of drugs and alcohol (OR 112.2 (95% Cl: 14.1-892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No increased risk for road trauma was found for drivers exposed to cannabis. The study concludes that drug use, especially alcohol, benzodiazepines and multiple drug use and drug-alcohol combinations, among vehicle drivers increases the risk for a road trauma accident requiring hospitalisation.
Drug development today needs to balance agility, speed and risk in defining the probability of success for molecules, mechanisms and therapeutic concepts. New techniques in functional magnetic resonance imaging (fMRI) promise to be part of a sequence that could transform drug development for disorders of the central nervous system (CNS) by examining brain systems and their functional activation dynamically. The brain is complex and multiple transmitters and intersecting brain circuits are implicated in many CNS disorders. CNS therapeutics are designed against specific CNS targets, many of which are unprecedented. The challenge is to reveal the functional consequences of these interactions to assess therapeutic potential. fMRI can help optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving success rates and reducing risk, development times and costs of drug development.
Biological rhythms are highly disrupted by night shiftwork (NSW), and any perturbation of social and family life negatively affects performance efficiency, health and social relations. These undesirable aspects have acute and chronic components. The effects manifest themselves not only as increased accidents' frequency, but also as sleep disturbances, excessive daytime sleepiness, psychosomatic disorders that may variously interact to configure a "shift-lag" syndrome, with acute and chronic manifestation. Chronic effects increase the risk of psychoneurotic, cardiovascular and gastrointestinal diseases. The effects of NSW on women are much more pronounced because of their reproductive function and family obligations. Recent Italian legislation (1999, 2003) on night-work has essentially recognised it as a new risk factor and has established that workers' health should be safeguarded through preventive check-ups and regular controls by occupational health physicians. This involves that now occupational health physicians are required to inform workers on coping strategies, and carefully assess health disorders with absolute or relative contraindications. Data from international literature and from our group production are revised and discussed.
Many patients with schizophrenia or bipolar disorder experience disturbances in their sleep-wake cycle, which may be a result of the disorder itself, of pharmacotherapy, or of a comorbid sleep disorder. These sleep disruptions can seriously impair patients' functioning as well as their quality of life. Therefore, accurate assessment of sleep problems is essential to appropriately treat patients and promote symptomatic remission. Sedating antipsychotics may ameliorate sleep disturbances, as well as agitation or other behavioral emergencies; however, these agents may also sedate patients to the point of dissatisfaction with the medication and/or impaired functioning, which may, in turn, increase treatment noncompliance and nonadherence. Using short-term adjunctive medications, such as benzo-diazepines or hypnotic agents, with a nonsedating antipsychotic to alleviate sleep disturbances is a reasonable treatment option for patients with schizophrenia or bipolar disorder. Overall, the pharma-cokinetics and pharmacodynamics of atypical antipsychotics are important factors to consider in the risk-benefit analysis, as are dosing strategies and individual patient factors, and clinicians must decide which agents are most appropriate for which patients.
Research relative to the efficacy of a therapeutic agent commands a clinician's greatest interest, but treatment decisions are made based on optimizing efficacy and tolerability/safety considerations. Second-generation atypical antipsychotic drugs are a study in the importance of taking a careful look at the full benefit-risk profile of each drug. The disorders that atypical antipsychotics are approved to treat--schizophrenia, schizoaffective disorder, and bipolar disorder--are associated with an increased rate of certain medical comorbidities compared to the general population. Between-drug differences in efficacy are relatively modest for the atypicals, or between atypicals and conventionals, while differences in safety and tolerability are larger and more clinically relevant. The current article will provide a brief summary of safety-related issues that influence treatment outcome and choice of drug.
The role played by psychoactive substances in road safety has become object of increasing interest: these substances can reduce driving performance and increase accidents risk. Aims of the study are to establish the dimension of the problem and to describe the characteristics of people involved in accidents under psychoactive substance effects.
Target population consists of people from 18 to 60-years-old involved in accidents afferent in Emergency Rooms. Subjects were interviewed by surveyors and a urines was collected for psychoactive substances screening.
In 18.5% of people we found substance consumption. Cocaine was the most frequently detected substance (9.5%), then benzodiazepines (7.5%), methadone, morphine and marijuana (THC) (3.5%). In 5.5% of subjects more than one substance was found. Considering only illegal substances detected, female have a higher risk to be consumers (OR = 1.36) and the young age (18-35 years) seems to be at higher prevalence and risk for substance use (OR = 1.86).
Considering all psychoactive substances detected, clearly the problem about substances consumption and driving is not restricted to youngest but involves all age groups.
In order to decrease the number of accidents due to substance use, new prevention programmes able to involve also middle age groups should be planned.
The anticholinergic actions of antidepressants can have undesirable effects that affect patient’ well-being. These effects can be peripheral or central in origin. The most frequently occurring anticholinergic effects are sedation, psychomotor and memory impairment, dry mouth and blurred vision.
One of the most prominent central anticholinergic effects is that on cognitive function. Effects that occur after a single dose consist of sedation (lowering of activation and arousal), psychomotor impairment [slowed sensorimotor processes that can adversely affect operational manual control (e.g. car driving)] and memory disturbances (forgetfulness, inability to store and retrieve information and recall events). After long term administration, tolerance to sedation and psychomotor impairment is likely to develop, but not to memory disturbances.
Elderly patients can be assumed to be particularly sensitive to central anticholinergic effects on cognitive functioning and also to peripheral anticholinergic effects such as dryness of the mouth and loss of accommodation in the eye. It is argued that for this reason, prescription of the classical tricyclic antidepressants should be avoided in elderly depressed patients. The second generation, or atypical antidepressants, and the newer selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are considered to be useful alternatives to tricyclics in elderly patients. These drugs possess greatly diminished anticholinergic activity, although the atypical antidepressants are very sedative and the effects of long term administration of SSRIs on cognition have rarely been studied. Another approach to avoiding anticholinergic effects is to use reversible inhibitors of monoamine oxidase (MAO)-A (RIMAs), such as moclobemide. These agents can attenuate scopolamine-induced cognitive dysfunction.
An important point in managing and avoiding anticholinergic effects of antidepressants is to realise that not all so-called ‘anticholinergic effects’ are actually cholinergically determined. Many other pharmacological effects of antidepressants, such as antihistaminergic and anti-α1-adrenergic effects, can induce sedation, cognitive and psychomotor impairment, blurred vision and dry mouth.
Assessed the capacity of a 60-min nap to reverse the sedating and performance-disruptive effects of ethanol, triazolam, and Diphenhydramine. 12 healthy, young men received (at 0800 to 0830) .6 g/kg ethanol and a placebo pill, .25 mg triazolam and ethanol placebo, 50 mg Diphenhydramine and ethanol placebo, and a placebo pill and ethanol placebo on each of 2 days in a Latin Square design. On 1 treatment day (at 0900 hour) Ss were allowed a 60-min nap and on the other a sleep latency test (no nap). The nap reversed the sedative effects of ethanol and Diphenhydramine and reduced those of triazolam. The nap reduced the performance-disruptive effects of ethanol and Diphenhydramine but not those of triazolam. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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 and 2.0 mg orally), and placebo across the range of E. Tulving's memory "systems" (1985; E. Tulving & D. L. Schacter, 1990) and on indices of arousal and attention. The authors obtained a similar, dose-dependent time course of sedation and attentional impairment following active drugs. The effects of SP and lorazepam were qualitatively indistinguishable on tasks tapping working, episodic, semantic, and procedural memory. However, they had a differential effect on word-stem completion: Whereas SP did not affect this, lorazepam produced a deleterious effect that was not dose dependent. This difference between SP and lorazepam on word-stem completion appears to be over and above the drugs' effects on sedation and attention. The authors' findings are discussed in terms of possible distinct neurobiological systems mediating different memory systems. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The safety of sedative antidepressants is a topical issue in the treatment of depression, with driving impairment being of particular concern. We have recently completed a study with normal male volunteers comparing the actions of dothiepin (a traditional, sedating antidepressant) with those of fluvoxamine (one of the selective serotonin re-uptake-inhibiting SSRI class of newer antidepressants) on psychomotor functions relevant to driving. We set out to investigate whether these drugs impair visual selective attention (focused and divided) by employing the 'odd-ball' task. Subjects were required to respond to letters of the alphabet (T for target and other letters for non-targets) that were presented at the centre and/or periphery of the computer screen. The task has been shown to be useful in detecting differences between drugs in their effects on selective attention. Preliminary results show that dothiepin delayed responses to single targets compared with fluvoxamine and placebo. There was also preliminary evidence that it mainly affected response times to peripheral targets. Furthermore, there was preliminary evidence that both drugs delayed responses to central targets compared with placebo on the divided attention trials. Finally, response accuracy in detecting peripheral targets was greater under placebo compared with fluvoxamine and dothiepin. The impairment produced by dothiepin is presumably a consequence of the central blockade of cholinergic muscarinic or histaminergic H1 receptors. It could contribute to the reported association between the tricyclic class of antidepressants and road traffic accidents, and would be worth further investigation in depressed patients taking both classes of drug.
Falls are the most common accidents among the elderly, and while medical risk factors are well known, less is known about the association of falls with social factors. The aims of this study were to estimate the incidence rate of falls in a national, representative sample of Israeli elderly and to examine the association of falls with selected medical and social factors. A special national survey conducted in 1985 by the Israel Central Bureau of Statistics showed that among a representative sample of 3,494 community-dwelling elderly persons aged greater than or equal to 65, 24% reported a fall in the past year; the rate was 16% among men and 31% among women. The majority of falls reported happened out of doors. Of those who fell 37% subsequently visited the emergency room. Analyses adjusted for age and sex showed that single persons, particularly women, living alone reported falls at a higher rate than their married counterparts. Analyses adjusted for age, sex and mobility level showed that frequency of social interaction was inversely related to reported falls. Use of sleeping pills, problems with vision, and mobility restrictions were associated with falls in age- and sex-adjusted analyses. Advanced age (greater than 75 years) was associated with repeated falls that occurred both in the home and outdoors.
Background. This study was performed in order to evaluate the short-term efficacy and safety of fixed risperidone doses compared to haloperidol.
Method. In a multi-national, parallel-group, double-blind study, patients with chronic schizophrenia(DSM—lllâ€w”eRre) randomlyassignedto risperidone1, 4, 8, 12 or 16 mg or haloperidol 10 mg daily for 8 weeks. Efficacy was assessed by the Positive and Negative Syndrome Scale for schizophrenia(PANSS) and clinicalglobal impression(CGI), andsafetyprimarilybytheExtrapyramidaSlymptomRatingScale(ESRS).
Results. One thousand three hundred and sixty-two patients were evaluated. The
optimumrisperidonedoseswere4mg and8mg,withresponseratesof63.4% (56.8%; 69.7%) and 65.8% (59.2%; 71.9%) respectively. Response rate in haloperidol-treated patients was 58.7% (52.0%; 65.3%); the 95% confidence intervals (Cl) of the differences between risperidone 4mg or 8 mg and haloperidol were (â€4”.3%; 13.7%) and(—1.9%; 16.0%) respectively.TherewerenosignificantdifferencesinCGIscores at endpoint between risperidone 4mg, 8 mg, 12 mg and 16 mg and haloperidol (3.0, 3.0, 3.2, 3.1 and 3.1 respectively); the 95% Cl of the differences between risperidone 4mg or8mg andhaloperidolwere(—0.4;0.1) and(—0.3;0.2) respectively.Meanshifts to the maximum total ESRS scores versus baseline (mean (confidence interval)) were significantlygreater in haloperidol-treatedpatients (5.1(4.0; 6.2)) than in the risperidone 1, 4, 8 and 12mg groups (1.1 (0.3; 1.9); 1.8(0.9; 2.7); 2.7 (1.8; 3.6) and 3.2 (2.3; 4.1) respectively (P< 0.05)).
Conclusion. Risperidone is an effective antipsychotic for the treatment of chronic
schizophrenia; doses of 4 and 8 mg seem to be optimal and have a lower incidence of side-effects than haloperidol.
The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.
Drugs may be the most frequent single cause of delirium, and very often they are a critical element in a multifactorial aetiology. While delirium may be precipitated by virtually any drug, certain classes of drugs are more commonly implicated.
Effective management of drug-induced delirium involves recognition, cessation or dosage reduction of the causative drug(s), and initiation of reorientation strategies and supportive medical care. Specific ‘antidotes’ are appropriate in only a few limited cases.
Drug treatment aimed at sedation should be introduced for specific indications, such as aggression, risk of harm to self or others, hallucinations, patient distress, and where compliance with therapy or procedures is essential. Certain benzodiazepines (diazepam, lorazepam, midazolam) and/or haloperidol may be the most appropriate choices in these circumstances.
Primary prevention requires the prescription of alternative lower risk medications and the minimisation of polypharmacy. Secondary prevention may be achieved through improved recognition of the condition.
Drugs are a frequently cited cause of dementia. There is a paucity of data regarding the incidence of drug-induced dementia, but it has been estimated that over 10% of patients attending memory clinics have iatrogenic disease. Drugs may impair cognition indirectly via metabolic effects, such as hypoglycaemia, by alterations of immunological factors within the CNS, and by actions that interfere with synaptic transmission. Classes of drugs most frequently responsible are the benzodiazepines, antihypertensives and drugs with anticholinergic properties. Each of these classes is likely to produce a different pattern of neuro-psychological deficits. Prevention of drug-induced dementia will be aided by: (i) minimising the number of drugs prescribed; (ii) using shorter-acting preparations; (iii) avoiding agents that cross the blood-brain barrier where possible; (iv) evaluating renal and hepatic function regularly; and (v) briefly assessing cognitive function before treatment.
First-generation histamine H1-receptor antagonists, such as diphenhydramine, triprolidine, hydroxyzine or chlorpheniramine (chlorphenamine), frequently cause somnolence or other CNS adverse effects. Second-generation H1-antagonists, such as terfenadine, astemizole, loratadine and cetirizine, represent a true advance in therapeutics. In manufacturers’ recommended doses, they have a more favourable benefit/risk ratio than their predecessors with regard to lack of CNS effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Rarely, some of the newer H1-antagonists may cause cardiac dysrhythmias after overdose or under other specific conditions. The concept of a risk-free H1-antagonist is proving to be an oversimplification. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use. The magnitude of the beneficial effects of each H1-antagonist should be related to the magnitude of the unwanted effects, especially in the CNS and cardiovascular system, and a benefit-risk ratio or therapeutic index should be developed for each medication in this class.
Objective.
—To examine the amount of inappropriate drug prescribing for Americans aged 65 years or older living in the community.Design.
—Cross-sectional survey of a national probability sample of older adults.Setting.
—The 1987 National Medical Expenditure Survey, a national probability sample of the US civilian noninstitutionalized population, with oversampling of some population groups, including the elderly.Subjects.
—The 6171 people aged 65 years or older in the National Medical Expenditure Survey sample, using appropriate weighting procedures to produce national estimates.Main Outcome Measures.
—Incidence of prescribing 20 potentially inappropriate drugs, using explicit criteria previously developed by 13 United States and Canadian geriatrics experts through a modified Delphi consensus technique. Three cardiovascular drugs identified as potentially inappropriate were analyzed separately since they may be considered appropriate for some noninstitutionalized elderly patients.Results.
—A total of 23.5% (95% confidence interval [CI], 22.4% to 24.6%) of people aged 65 years or older living in the community, or 6.64 million Americans (95% CI, 6.28 million to 7.00 million), received at least one of the 20 contraindicated drugs. While 79.6% (95% CI, 77.2% to 82.0%) of people receiving potentially inappropriate medications received only one such drug, 20.4% received two or more. The most commonly prescribed of these drugs were dipyridamole, propoxyphene, amitriptyline, chlorpropamide, diazepam, indomethacin, and chlordiazepoxide, each used by at least half a million people aged 65 years or older. Including the three controversial cardiovascular agents (propranolol, methyldopa, and reserpine) in the list of contraindicated drugs increased the incidence of probably inappropriate medication use to 32% (95% CI, 30.7% to 33.3%), or 9.04 million people (95% CI, 8.64 million to 9.44 million).Conclusion.
—Physicians prescribe potentially inappropriate medications for nearly a quarter of all older people living in the community, placing them at risk of drug adverse effects such as cognitive impairment and sedation. Although most previous strategies for improving drug prescribing for the elderly have focused on nursing homes, broader educational and regulatory initiatives are needed.(JAMA. 1994;272:292-296)
Increasing attention is being paid to inappropriate medication use in nursing homes. However, criteria defining the appropriate or inappropriate use of medication in this setting are not readily available and are not uniform. We used a two-round survey, based on Delphi methods, with 13 nationally recognized experts to reach consensus on explicit criteria defining the inappropriate use of medications in a nursing home population. The criteria were designed to use pharmacy data with minimal additional clinical data so that they could be applied to chart review or computerized data sets. The 30 factors agreed on by this method identify inappropriate use of such commonly used categories of medications as sedative-hypnotics, antidepressants, antipsychotics, antihypertensives, nonsteroidal anti-inflammatory agents, oral hypoglycemics, analgesics, dementia treatments, platelet inhibitors, histamine2 blockers, antibiotics, decongestants, iron supplements, muscle relaxants, gastrointestinal antispasmodics, and antiemetics. These criteria may be useful for quality assurance review, health services research, and clinical practice guidelines. The method used to establish these criteria can be used to update and expand the guidelines in the future.(Arch Intern Med.1991;151:1825-1832)
To determine whether cyclic antidepressants increase the risk of hip fracture, we conducted a population-based casecontrol study in the Canadian province of Saskatchewan. We identified 4501 persons 65 years of age or older with a first hospitalization for hip fracture between 1977 and 1985 and 24 041 comparable controls. Current antidepressant users had a relative risk of hip fracture of 1.6 (95% confidence interval, 1.3 to 1.9). Medical record review for a sample of 164 cases suggested this finding was not due to confounding by body mass, impaired ambulation, functional status, or dementia.(Arch Intern Med. 1991;151:754-756)
The treatment of psychotic illness has long been inextricably associated with society's view in general on social deviance. In medieval times, psychotic individuals were contained within the community, a situation which still prevails in many developing countries. Aggregation of such patients in asylums followed the increasing industrialization of communities in the nineteenth century, when the ability of the disadvantaged of all kinds to survive was greatly jeopardized. The twentieth century has seen a gradual reversal of this process, as attitudes towards mentally ill people have become a little more enlightened and liberal. However, the swing against the great lunatic asylums of the last century has proceeded at such an administrative rate that our patients are again in danger of succumbing medically and economically within our communities. It is common to see desperately poor and damaged psychotic individuals on our streets. The advent of neuroleptics was a major factor in the change from a custodial to an ostensibly rehabilitative approach in the treatment of schizophrenia. However, classic neuroleptics have a long list of well-recognized side effects such as affective and cognitive impairment that lead to poor treatment compliance, psychiatric relapse and social decompensation, the state of affairs of our street psychotics. Treatments that lessen the probability of this unfortunate process are desperately needed. The introduction of new neuroleptic drugs with favourable side effect profiles is to be welcomed as a major step in increasing the quality of life of our patients, both in hospital and functioning in the community.
The following article summarizes the background to a British Association for Psychopharmacology Workshop held at the Royal Society, London, on 15 March 1996. It includes abstracts of the papers presented at that meeting and concludes with a list of agreed guidelines for future studies with antipsychotic drugs in healthy volunteer subjects.
Much controversy has surrounded triazolam since it was marketed in the late 1970s. In spite of ongoing debate no major pharmacoepidiomological study has been published, comparing triazolam to other benzodiazepines (BZD). The present study examines the occurrence of medical events after a prescription for one of five BZD. Data was obtained from the Saskatchewan Health Data Bases on all persons who received a prescription for one of triazolam, flurazepam, oxazepam, lorazepam or diazepam, not having had a prescription for any of these in the previous six months. These persons were monitored for eight types of medical events. (1. suicides and attempts, 2. depression, 3. other psychiatric condition, 4. traffic accident injury, 5. injury due to falls, 6. injury due to poisoning, 7. seizures, 8. allergic reactions) for three weeks after their prescription for the BZD. Rates for medical events were compared to those in an unexposed population sample. It was concluded that, on the whole, triazolam does not appear to show a record of hospitalization worse than the other five BZD tested. In general, BZD should be used cautiously, judiciously and at the lowest possible dose.
The effects on memory, psychomotor performance and mood of two dosage regimens of befloxatone, a new reversible and selective MAO-A inhibitor were assessed in a randomized, double-blind, cross-over, placebo-controlled study involving 12 healthy young male volunteers. Befloxatone and a placebo were orally administered as single (5 and 10 mg) and repeated doses (10 mg once daily and 5 mg twice daily) at one week wash-out intervals. Objective tests evaluated both memory (working memory, immediate and delayed free recall of a word list, dual coding and faces recognition) and vigilance continuous performance task (CPT), and digit symbol substitution (DSST). Subjective mood and sleep were assessed using visual analogue scales and the Leeds Sleep Evaluation Questionnaire. Statistical analysis was conducted using an ANOVA with pairwise comparisons using the Student Newman Keuls procedure.
Both dosage regimens of befloxatone (10 mg once daily or 5 mg twice daily) were free of any detrimental effect on vigilance (CPT) and information processing (DSST) and did not significantly disrupt short- and long-term memory (working memory, free recall of words, dual coding and faces recognition). In addition, no subjective sedation or sleep disturbances were recorded.
In conclusion, this study gives no evidence to suggest that befloxatone, at a daily dose which shows potent MAO-A inhibition, has any sedative or amnestic properties likely to interfere with the activities of everyday-life in young subjects and therefore may be safely administered in depressed outpatients.
Sixty-six elderly depressed patients received fluoxetine 20 mg (FLU) or amitriptyline 75 mg (AMI) for 42 days in a double blind parallel group study. Each week, subjects completed a test battery which is sensitive to the residual effects of psychoactive drugs. The results show that FLU and AMI were equally effective in relieving depression. However, the psychometric test battery showed that, compared to FLU, AMI, as expected, produced impairments in cognitive function and psychomotor performance. The relative impairment of cognitive and psychomotor skills following the tricyclic AMI and the lack of such activity after administration of the selective serotonin reuptake inhibition, FLU are important considerations when prescribing antidepressants, especially when the safety and well being of ambulant patients is essential.
Antidepressant medications have been in general use since the late 1950s. Many patients are treated as outpatients and often continue with their normal routines during treatment. Individuals may undertake activities where any change in memory functioning, negative or positive, might have important consequences. Furthermore, many antidepressants have similar efficacy. Information about differential effects upon memory would seem valuable information for the clinician to have at his or her disposal. This paper reviews available evidence on the effects of antidepressants on human memory. Many studies have involved the single or short-term administration of antidepressants to healthy volunteers, thereby not acknowledging that depression per se has a negative impact on memory processes. Even in the studies on patient samples, groups very with regard to type and severity of depression, dosage and duration of treatment. Limited evidence, however, does suggest that antidepressants may exert differential effects upon memory functioning which could be predicted from their action on specific neurotransmitter system.
Recent medication use of 3,394 members of the Group Health Cooperative of Puget Sound (GHC) diagnosed with an incident work-related injury was compared to that of two controls selected from the GHC membership and matched on age, gender, and Standard Industrial Classification Code of their employer. Medication use was determined from the GHC pharmacy data base. The injuries of the cases included 496 fractures or dislocations, 2, 728 open wounds, crushing injuries, or superficial injuries, 176 burns, and 64 internal or intracranial injuries. The risk of injury was elevated among users of antihistamines [odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-1.9], antibiotics (OR = 1.2, 95C% Cl = 1.0-1.5), and diabetes medications (OR = 1.3, 95% CI = 0.9-1.9). The patterns of risk were similar for males and females, but varied by type of injury. No consistent associations between use of antidepressants, antianxiety medication, or narcotics and work-relaled injury were observed. The use of some medications, or conditions requiring medications, may contribute to the risk of a work-related injury. © 1996 Wiley-Liss, Inc.
Tranquilizers, and specifically benzodiazepines (BZD), have become one of the most widely used group of drugs in the world; some have suggested too widely used. Interest in these drugs in still extremely high, both from the scientific and sociological point of view. This is best documented by the fact that the present review is based on more than 700 articles published between 1981 and 1984 covering various aspects of clinical pharmacology. Pharmacodynamic studies are mostly concerned with effects of the drug on the central nervous system (CNS), as well as on behavious and neuroendocrine functions. The former include computer-assisted quantitative analyses of the scalp-recorded wake electroencephalogram (EEG), based on which it seems possible to determine if, how, when and at what dose a newly developed compound affects the human brain. Sleep investigations are now concerned not only with the effect of the drug on the all-night sleep, but also on the quality of awakening and early morning behaviour as well as with residual effects during daytime, affecting amnestic and cognitive functions, psychomotor performance (specifically in regard to driving ability), as well as mood and affectivity. Finally, for almost a decade increasing concern has been expressed about the widespread use of tranquillizers in society. Scientific evidence concerning thiss issue will be reviewed so that an appropriate medical decision may be reached for the treatment of the individual patients after consideration of the beneficial effects as well as undesirable side-effects.
An extensive review of the literature was performed in order to identify those psychometric variables and conditions which have proved to be sensitive to the CNS effects of antihistamines. It is hoped that the result of this review will allow the formulation of a series of guidelines which would be useful both to researchers, when deciding on the methodology of future trials, and to readers when assessing the validity of a particular volunteer study with a antihistamine.
The main purpose of this study was to compare the sensitivity of a driving simulator test model (TS2) with a standard on-the-road driving test, after one night treatment with lormetazepam 1 mg, oxazepam 50 mg (as a verum) and placebo. The secondary purpose was to measure the effects of the intended drugs and placebo in the same subject sample, after two treatment nights in the morning and in the afternoon, on on-the-road driving performance. Eighteen healthy male volunteers received the three treatments (2 consecutive nights each) according to a double-blind, three-way crossover design. Time of administration was set at 22.00 hours each night. An on-the-road driving test and a simulator driving test were conducted in the morning following the first night. After the second treatment night, on-the-road driving tests were performed in the morning and in the afternoon. The on-the-road driving test consisted of operating an instrumental automobile over a 100 km highway circuit at a constant speed (90 km/h) and constant steady lateral position between the right lane boundaries. Primary performance measure was the SD of lateral position (SDLP). The simulator test consisted of repeatedly performing ‘curve-following’ manoeuvres, which was the main tracking control task, while simultaneously reacting to secondary visual signs. Test parameters were the number of correctly executed manoeuvres (TC) and reaction time (RT). Oxazepam 50 mg seriously impaired, and lormetazepam 1 mg slightly impaired, on-the-road driving performance in the morning, both after the first and second treatment night. The drugs produced no significant effects in the afternoon test following the second night. In contrast with these results, neither oxazepam 50 mg nor lormetazepam 1 mg affected simulator tracking control after one night. No deterioration was found for reaction time. Correlational and multiple regression analyses were applied to determine relationships between SDLP, TC and RT. The major conclusion of this study was that the TS2 driving simulator test does not predict residual drug effects in the on-the-road driving test, and seems to be a less sensitive measure of sedative drug-induced impairment in contrast to the on-the-road driving test.
The human amnestic syndrome associated with lesions of the hippocampus and amygdala is characterized by a selective impairment of recent (explicit, episodic) memory. Benzodiazepine (BZ) treated normal subjects demonstrate similar, marked impairments in episodic memory, but in addition, BZ also induces sedation and inattention. Thus, the amnestic effects of BZ may be secondary to drug-induced sedation. However, when subjects were pretreated with the specific BZ receptor antagonist, flumazenil, the sedative and attentional effects of diazepam were blocked, but a marked impairment in episodic memory still occurred. This demonstrates that, using neuropharmacological methods, it is possible to produce a dissociation of memory impairment from inattention and sedation. Such distinct patterns of cognitive dysfunction may serve as models for clinical cognitive syndromes.
No longer prescribed only for vegetative signs of depression, tricyclic antidepressants also lessen depressive cognitive distortions. Less clear is whether they ameliorate depressed patients' other cognitive deficits in memory, information processing speed, and psychomotor performance. We tested the alternative hypothesis that amitriptyline, because of its anticholinergic and sedative properties, would exacerbate depressed patients' cognitive disturbances. Depressed outpatients received double-blind placebo (n=15), amitriptyline (n=10), or clovoxamine fumarate (n=10), a serotonin reuptake inhibitor relatively lacking in anticholinergic properties. Depression, memory, and psychomotor performance were assessed at baseline and after 7 and 28 days of drug treatment. Depression was alleviated after all treatments, including placebo. Only amitriptyline impaired performance on tests of memory, producing a significant decrement, relative to placebo, after 4 weeks of treatment. None of the treatments adversely affected performance on psychomotor tasks. These findings add to the evidence that antidepressant drugs with high anticholinergic activity can impair memory, despite alleviation of depression.
The effects of 0.2 mg/kg orally administered diazepam and of a placebo on explicit memory, implicit and knowledge memory were assessed using a free recall task, a word-stem completion task and two category-generation tasks. Twenty four healthy volunteers took part in this double-blind study. Diazepam impaired explicit but not implicit memory. The drug also spared knowledge memory. Explicit memory was linked with the diazepam-induced sedation and with the self-rated affective load of to-be remembered words, but implicit memory was not. The diazepam-induced dissociation between explicit and implicit memory supports the notion of two distinct forms of memory and reproduced the dissociation observed in organic amnesia.
The effects of befloxatone (20 mg o.d. for 10 days) alone and in combination with ethanol on psychomotor performance, memory and mood were assessed in a randomized, double-blind, placebo controlled study. On treatment days 6, 8 and 10, subjects received 0.5 and 0.8 g/kg ethanol and ethanol placebo in randomly assigned, balanced orders, 2 h post-drug. Critical fusion frequency, choice reaction time, postural instability, critical tracking and mood were measured 1h before ethanol and 1, 3 and 5 h afterwards. Divided attention, sustained attention and memory (immediate and delayed recall) were also measured in single tests, 2.5-5 h post-ethanol.
Ethanol's effects were generally significant when blood alcohol concentrations (BAC) after both doses were the highest; i.e. 0.48-0.67 and 0.96-1.10 mg/ml. Those effects were virtually gone after the subjects' mean BACs fell below 0.40 mg/ml. Befloxatone alone had no significant impairing effect in any test. Neither did it significantly interact with ethanol to cause any greater impairment than the latter alone. It was concluded that befloxatone does not potentiate the sedating and impairing effects of ethanol.
Both antipsychotic and anticholinergic drugs have been implicated in the production of the memory deficits seen in schizophrenia. We compared the effects of chlorpromazine (50 mg) and benzhexol (5 mg) with placebo on a battery of tests of memory, psychomotor function and mood, in 12 healthy volunteers. Benzhexol, but not chlorpromazine, impaired both word recall and word recognition. Neither drug had an effect on long-term memory Both active compounds were associated with self-rated sedation, and chlorpromazine produced impairment in saccadic eye movements. This study supports the contention that sedation is unlikely to be the mechanism by which anticholinergic drugs exert their amnestic effect.
Fifteen healthy male volunteers received single doses of 100 mg immediate release remoxipride (IR), 150 mg controlled release remoxipride (CR), 50 mg chlorpromazine (CPZ), 2 mg lorazepam (LZ), and placebo in a randomised, five-period cross-over study. Both saccadic (SEM) and smooth pursuit eye movements (SPEM) as well as a battery of psychomotor performance tests were assessed at 1.5-h intervals over 9 h following drug administration. The areas under the response-time curves and the maximum effect during the study period were analysed by analysis of variance. The most consistent impairments were produced by LZ. The neuroleptics caused impairments to SEM, and tended to impair critical flicker fusion, continuous attention and both paced and unpaced versions of the digit-symbol substitution test as well as subjective measures of sedation. Only LZ impaired SPEM. Neither paced nor unpaced psychomotor tests distinguished between neuroleptics and benzodiazepines. The low therapeutic doses of IR and CR produced similar impairments to a sub-therapeutic dose of CPZ. Selectivity of pharmacological action does not appear to predict selectivity of effect on psychomotor function.
Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a randomized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1- week wash-out interval. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitant administration on days 7 or 9 of each treatment period. Psycho motor performance and cognitive function were evaluated before and 2, 4, 6 and 8 h post-dose, using objective tests [critical flicker fusion threshold (CFF), choice reaction time (CRT), digit-symbol substitution (DSST), body sway and short-term memory (Sternberg memory scanning)] and self-ratings [line analogue rating scales: (LARS)]. Long-term memory (delayed free recall and recognition of pictures) was assessed before the dose and 2 and 4 h post-dose. Pharmacodynamic interactions were evaluated by applying repeated measures ANOVA to a 2 x 2 factorial interaction model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, information processing or memory. In contrast, a single 2 mg dose of lorazepam induced marked impairment of psychomotor performance and cognitive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post-dose, depending on the test used. In addition, lorazepam induced anterograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On the contrary, alpidem significantly antagonized the lorazepam-induced CRT increase and anterograde amnesia, and produced similar trends on most of the other cognitive parameters; thus, the results obtained with the combination of alpidem and lorazepam consistently indicated less impairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem at the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agonist.
The persistence of deficits in cognitive performance in major depressive patients taking maintenance antidepressant medication was assessed by examining groups of patients in clinical remission, stable on one of a range of tricyclics or selective serotonin re-uptake inhibitors (SSRIs) for at least 3 months, compared with controls. Measures of critical flicker fusion (CFF), choice reaction time (CRT), subjective sedation, and anticholinergic side-effect score were made. Tricyclic antidepressants (TCAs) produce a significant deficit in critical flicker fusion threshold compared both to controls and SSRIs. Similar effects were seen with choice reaction times which were significantly affected by age. Sedation scores were significantly higher with TCAs than SSRIs. Anticholinergic side effects were strongly related to CFF, less so to visual analogue sedating scales and not significantly to CRT. The effect measured by CFF is different from sedation, and may be related to the anticholinergic potency of the drug; it may be considered a drug-induced pseudodementia. This effect represents a risk factor for accidents during maintenance therapy and may impair work and leisure performance. The relative risk of weight gain with TCAs compared to SSRIs in women was 5.92 (95% CI 1.79-19.50).
Effects on human performance of remoxipride (RX), an antipsychotic drug of substituted benzamide structure, were studied in a randomized double-blind crossover trial where 12 young healthy volunteers took at 1 week intervals single oral doses of placebo or remoxipiride 100 mg both alone and in combination with 15 mg diazepam (DZ) or 0.8 g/kg ethanol (EtOH). Objective (digit symbols, tracking, choice reaction, flicker fusion, Maddox wing, body balance, memory) and subjective (visual analogue scales, questionnaire) tests were administered at baseline and 1.5, 3, 4.5 and 6 h post-treatment.
Of 1042 individuals aged 65 years and over who were successfully interviewed in a community survey of health and physical activity, 35% (n=356) reported one or more falls in the preceding year. Although the overall ratio of female fallers to male fallers was 2.7: 1, this ratio approached unity with advancing age. Mobility was significantly impaired in those reporting falls. Asked to provide a reason for their falls, 53% reported tripping, 8% dizziness and 6% reported blackouts. A further 19% were unable to give a reason. There was no association between falls and the use of diuretics, antihypertensives or tranquillizers, but a significant association between falls and the use of hypnotics and antidepressants was found.
Discriminant analysis of selected medical and anthropometric variables indicated that handgrip strength in the dominant hand and reported symptoms of arthritis, giddiness and foot difficulties were most influential in predicting reports of recent falls.
Before and after its introduction in 1987, zopiclone was the object of investigation in 16 psychometric studies employing both healthy volunteers and insomniac patients. Their common purpose was to determine whether nocturnal doses (usually the standard 7.5 mg) possess residual sedative effects that interfere with skilled safety-relevant performance, such as car driving, over the following day. Most studies have found no residual effects. Those that did, have shown them to be modest in magnitude and not to persist for longer than about 12 hours from the time of dosage. Without altering the general conclusion that zopiclone possesses few if any residual effects of clinical relevance, it must be said that the studies reviewed failed to meet current methodological standards and may have left some important questions unanswered.
The effect of zopiclone (7.5 mg) on attention, vigilance and memory components was evaluated during a nocturnal period in comparison to a placebo, to zolpidem (10 mg) and to flunitrazepam (1 mg) in a double blind, randomized study, after administration of a single dose in 16 young healthy volunteers. It appears that there is a clear effect on attention and vigilance; this effect is apparent during the kinetic phase of the absorption of the medication. The effect on memory is transient and is absent four hours after the ingestion of the drug. The objective results are not strictly consistent with the chronology of the subjective parameters (Leeds scale - Visual Analogue Scale). The three hypnotics under comparison do not fundamentally differ except in their kinetic/pharmacodynamic effect relationship. One important fact, taking the parameters as a whole, is that there is no objective "residual" effect.
Forty paid healthy male students participated in two subacute experiments of 6 weeks each. In the first trial 20 of them received bromazepam, thioridazine, and placebo double blind cross over for 2 weeks each, and in the second trial the active agents administered to the other 20 participants were chlorpromazine and sulpiride. The tests used were paired associate learning with nonsense syllables and digit memory span. Before testing the subjects took either an alcoholic or a nonalcoholic bitter drink.
As in the the previous study from this laboratory, alcohol was found to impair learning capacity. Of the drugs used only bromazepam impaired learning significantly, and the combined effect of alcohol and bromazepam on learning capacity was very deleterious. The adrenolytic effect of drugs did not correlate with their effect on learning. Caution is necessary when prescribing bromazepam for active outpatients at least in doses used in this study.
Twenty healthy subjects took amitriptyline, doxepin, and placebo for 2 wk each in a double-blind crossover trial, and another 20 subjects similarly took nortriptyline, chlorimipramine, and placebo. The antidepressants were given three times daily in doses generally used for neurotic patients. The presence of antidepressants in tissues was checked with the tyramine pressor test. On the seventh and fourteenth days of each period, psychomotor skills (choice reaction, coordination, and attention) were measured after the administration of drugs in combination with an alcoholic or placebo drink. Dose-response graphs for the tyramine pressor effect were shifted to the right during the antidepressant treatment, indicating a blockade of the membrane pump in peripheral sympathetic terminals. This antityramine effect of antidepressants did not correlate with their psychomotor effects. No drug alone importantly impaired psychomotor skills. Amitriptyline in combination with alcohol increased cumulative choice reaction times, and doxepin in combination with alcohol increased both cumulative choice reaction times and inaccuracy of reactions. Coordination was impaired after both of these combinations on the seventh day. It seems as if doxepin and amitriptyline but not nortiriptyline or chlorimipramine, in combination with 0.5 gm/kg of alcohol, may be especially dangerous in driving.
Studies on the behavioural effects of paroxetine on healthy young volunteers, elderly volunteers, and patients suffering from major depressive illness failed to show any evidence of detrimental effects on a battery of objective and subjective measures even when alcohol was taken. In contrast, the chosen verum, amitriptyline or lorazepam, produced significant impairment. The study on depressed patients showed improvement in cognitive functions among the paroxetine group from the start, whereas these functions were, initially, significantly impaired in the dothiepin group. Moreover, the Leeds Sleep Evaluation Questionnaire indicated that dothiepin produced, with respect to paroxetine, a significantly poorer quality of sleep.
To determine whether commonly used psychoactive drugs increase the risk of involvement in motor vehicle crashes for drivers > or = 65 years of age, the authors conducted a retrospective cohort study. Data were obtained from computerized files from the Tennessee Medicaid program, driver's license files, and police reports of injurious crashes. Cohort members were Medicaid enrollees 65-84 years of age who had a valid driver's license during the study period 1984-1988 and who met other criteria designed to exclude persons unlikely to be drivers and to ensure availability of necessary study data. There were 16,262 persons in the study cohort with 38,701 person-years of follow-up and involvement in 495 injurious crashes. For four groups of psychoactive drugs (benzodiazepines, cyclic antidepressants, oral opioid analgesics, and antihistamines), the risk of crash involvement was calculated with Poisson regression models that controlled for demographic characteristics and use of medical care as an indicator of health status. The relative risk of injurious crash involvement for current users of any psychoactive drug was 1.5 (95% confidence interval (CI) 1.2-1.9). This increased risk was confined to benzodiazepines (relative risk = 1.5; 95% CI 1.2-1.9) and cyclic antidepressants (relative risk = 2.2; 95% CI 1.3-3.5). For these drugs, the relative risk increased with dose and was substantial for high doses: 2.4 (95% CI 1.3-4.4) for > or = 20 mg of diazepam and 5.5 (95% CI 2.6-11.6) for > or = 125 mg of amitriptyline. Analysis of data for the crash-involved drivers suggested that these findings were not due to confounding by alcohol use or driving frequency.
Serotonin uptake inhibitors are generally considered activating antidepressants. To assess rates and temporal patterns of activation and sedation as well as dose-effect relationships, adverse event data were evaluated from a fixed-dose study comparing placebo and fluoxetine 5, 20, and 40 mg/day in the treatment of major depressive disorder (N = 363) and two fixed-dose studies pooled together comparing placebo and fluoxetine 20, 40, and 60 mg/day in the treatment of major depressive disorder (N = 746). The adverse events nervousness, anxiety, agitation, and insomnia were considered indicative of activation; somnolence and asthenia were considered indicative of sedation. Activation and sedation were both statistically significant (p less than or equal to 0.05) treatment-emergent phenomena, but dose-effect relationships differed. Activation rates were relatively stable between 5 and 40 mg/day, and then increased at 60 mg/day. Sedation rates increased linearly to 40 mg/day and then were comparable at 40 and 60 mg/day. Discontinuations for either phenomenon were uncommon. The temporal patterns of first occurrences and persistence of activation and sedation differed. First occurrences of activation peaked early and declined over time with all doses. First occurrences of sedation also peaked early with all doses, but there may have been greater variability in first occurrences of sedation over time with lower doses. Persistent occurrences of sedation may decline less over time than persistent occurrences of activation.
We gave 24 healthy elderly volunteers with a perceived sleep onset of at least 30 minutes zolpidem 5 mg, zolpidem 10 mg, or placebo for 7 days in a double-blind, three-way, crossover study.
The morning after nocturnal dosing, psychomotor performance and cognitive ability were measured using tests which are sensitive to the residual effects of hypnotics and to the effects of drugs on various indicators of sleep quality. The tests were: Choice Reaction Time; Tracking; Critical Flicker Fusion Threshold; Memory Scanning; Word Recognition; the Leeds Sleep Evaluation Questionnaire and Line Analogue Rating Scales.
Zolpidem produced a subjective improvement in sleep but did not impair performance the following day. Furthermore, during repeated administration, there was no tolerance to the effects of sleep latency and quality of sleep, nor adverse effects on task performance.
The acute and sub-chronic effects of moclobemide and mianserin on driving and psychometric performance were compared to those of placebo in a double-blind, cross-over study involving 17 healthy volunteers. Mianserin, moclobemide and placebo were administered for 8 days. Subjects' performance was measured on days 1 and 8 of each treatment series; subjective sleep parameters, mood, and possible side-effects were recorded each treatment day on questionnaires or visual analog scales. Mianserin affected most of the performance measures, while moclobemide affected none; mianserin also impaired driving and tracking performance and decreased CFF. Whilst receiving mianserin, subjects reported depressed levels of alertness, calmness, and contentment; the quality of their sleep was unaffected, but its duration increased, together with feelings of drowsiness and fatigue during the day. No statistical interactions between the factors Drugs and (Treatment) Days were found, indicating that little pharmacological tolerance developed over time during mianserin treatment. Mianserin's sedative properties are held responsible for all performance and subjective effects of the drug. It is concluded that moclobemide 200 mg b.i.d. has no important sedative properties.
The respective effects of three antidepressant drugs (moclobemide, 450 mg/j; viloxazine, 300 mg/j; maprotiline, 150 mg/j) on vigilance, attention, and memory were compared. Young depressed outpatients (n = 46) entered a double-blind, randomized, monocentre clinical trial lasting for 6 weeks. Drug actions were assessed through the regular determination of critical flicker fusion point (CFF), reaction times (SRT), and a battery to measure memory components. None of the three drugs caused deterioration in cognitive functions. On the other hand, moclobemide improved both vigilance and attention (CFF, SRT) and some crucial components of memory (general memory scores, delayed word recall, recognition of familiar faces). This effect was rapid, stable, and superior to those of viloxazine and maprotiline. It may be explained by moclobemide's selective and reversible inhibition of monoamine oxidase A, as well as by the lack of any anticholinergic action.