bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent advances in the clinical pharmacology of benzodiazepines part I: Pharmacokinetics
Authors: Saletu B. , Pakesch G.
Published: December 2004

Tranquillizers, 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 is 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. Pharmacokinetic studies dealing with absorption, metabolism and elimination after acute and chronic administration demonstrate that the onset and duration of action of BZD after single oral doses depend largely on absorption rate and the rate and extent of distribution. The rate and extent of accumulation during multiple dosage depend on the elimination half‐life and clearance. A framework is proposed for classification of BZD according to the elimination half‐life. Various factors — such as age, sex, disease state and drug interaction — influence the pharmacokinetic properties of BZD. Pharmacodynamic studies are mostly concerned with effects of the drug on the central nervous system (CNS), as well as on behaviour 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 mnestic 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 this 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.
Tardive dyskinesia in schizophrenia and other disorders: Associations with ageing, cognitive dysfunction and structural brain pathology in relation to neuroleptic exposure
Authors: Waddington J. L.
Published: December 2004

Little is known of the processes which confer vulnerability to the emergence of involuntary movements (tardive dyskinesia) in only a proportion of patients receiving long‐term treatment with neuroleptic drugs. There is no consistent evidence that patients with involuntary movements have received either longer or more vigorous pharmacotherapy, and it has proved difficult to demonstrate any general relationship between increasing neuroleptic exposure and the emergence of the syndrome. Advancing age may be associated more with deleterious changes in the central nervous system within individual patients that can raise vulnerability to the emergence of involuntary movements, than with particular predisposing patterns of neuroleptic exposure. The literature in schizophrenic patients reveals that two indirect and putative indices of ‘organicity’, namely cognitive dysfunction and negative schizophrenic symptoms, together with several CT indices of structural brain pathology, show similar and robust associations with the presence of involuntary movements. In schizophrenia, predisposition to the emergence of involuntary movements during long‐term neuroleptic therapy appears intimately related with particular features of the illness, especially those associated with clinical deterioration. It is argued from clinical and animal studies that neuroleptics may hasten the appearance of dyskinetic movements in individuals with the greatest likelihood of ultimately having such movements spontaneously as cerebral deterioration proceeds.
Temazepam as a hypnotic in osteoarthritic patients
Authors: Leigh T. J. , Hindmarch I. , Bird H. A. , Wright V.
Published: December 2004

The effects of nocturnal temazepam elixir on 14 male osteoarthritic patients and 16 age‐ and sex‐matched healthy controls were investigated in a double‐blind parallel groups study. Temazepam produced a number of significant changes in objective sleep. In the osteoarthritic patients temazepam reduced the duration of awakenings, percentage stage 0, percentage stage 1, percentage stages (0+1) and increased percentage stage 2 and REM latency. In the controls temazepam reduced the duration of awakenings, percentage stage 0, percentage stages (0+1) and increased percentage stage 2, sleep efficiency and REM latency. During the drug period, seven out of 15 subjects receiving temazepam reported improved sleep, compared with one out of 15 placebo subjects. There was no evidence to suggest that temazepam caused any unwanted side‐effects or affected the duration of morning stiffness in osteoarthritic patients. Temazepam produced no significant impairment of early morning psychomotor performance or significant withdrawal effects in either patients or controls.
The effects of practice on measures of performance
Authors: McClelland G. R.
Published: December 2004

The effects of practice on a range of performance measures often used in studies of psychoactive drugs have been assessed in 50 normal healthy adult volunteers, during 10 practice sessions over an 8‐day period. There was no dramatic effect of practice on any of the parameters measured, only one of the mean values at the tenth session exceeded one standard deviation of the mean of the first session (manipulative motor task). Practice did not materially affect performance on elapsing time estimation, tapping rate, body sway measured by a ultrasonic method or rapid visual information processing task variables. There tended to be a non‐significant, exponential learning curve for choice reaction response and movement times to visual stimuli, flash fusion threshold and the manipulative motor task, with a statistically significant practice effect on all 16 visual analogue scales used; a plateau was apparently achieved by the fifth practice session for all these parameters. There was a statistically significant straight‐line improvement in digit span across the 10 sessions. It is concluded that for most simple measures of performance used in psychopharmacology including visual analogue scales, four pre‐study training sessions are necessary, and that direct methods of recording body sway are preferred to indirect methods such as the balance platform.
Antipsychotic properties of neuroleptic‐like neuropeptides in schizophrenia: A clinical review
Authors: Verhoeven W. M. A. , Van Ree J. M.
Published: December 2004

Recently much interest has been shown in the antipsychotic efficacy of neuroleptic‐like neuropeptides in schizophenia. In this article the clinical effects of the non‐opioid fragments of γ‐endorphin, the so‐called γ‐type endorphins DTγE and DEγE, are reviewed. In addition, preliminary clinical studies of peptides related to cholecystokinin are considered. It is concluded that γ‐type endorphins possess antipsychotic properties in a subgroup of patients who may belong to Type I schizophrenia. With cholecystokinin‐related peptides, in particular ceruletide, antipsychotic effects have been reported which seem to be more or less comparable to those observed with γ‐type endorphins.
Beyond the benzodiazepines: The search for new anxiolytics. A summary of pre‐clinical approaches
Authors: File Sandra E.
Published: December 2004

The clinical efficacy of the benzodiazepines in reducing anxiety is widely accepted. However, the search for novel anxiolytics continues, motivated by the hope of finding a non‐sedative anxiolytic. This article reviews the pre‐clinical evidence for new compounds as it relates both to their anxiolytic actions in animal tests and to their sedative potential. Drugs acting at sites on the GABA‐benzodiazepine receptor complex are discussed, as well as the potential importance of aminergic and peptidergic pathways.
A double‐blind placebo‐controlled trial of tanakan in the treatment of idiopathic cognitive impairment in the elderly
Authors: Wesnes K. , Simmons D. , Rook M. , Simpson P.
Published: December 2004

Fifty‐four elderly patients, living at home, completed a 3‐month, double‐blind, randomized, placebo‐controlled trial of the effects of Tanakan on both cognitive efficiency and the quality of life. Patients were included in the study if they showed mild signs of impairment in everyday function on the Crichton Geriatric Rating Scale. Cognitive efficiency was measured before and at monthly intervals during the trial using a battery of tests of mental ability comprising both computerized and pencil‐and‐paper tasks. The quality of life was assessed using a behavioural questionnaire which was administered before and after the study. Individual analyses of the cognitive tests showed some advantage of Tanakan over placebo, but when the accuracy scores from all eight tests were combined using two different techniques, although both groups improved over time, the improvement with Tanakan at week 12 was significantly greater than with placebo. No signs of improvement were detected with placebo when the reaction time measures were combined using these techniques, whereas by week 4 the Tanakan group were significantly faster than at baseline, and were superior to placebo throughout the study. These improvements in mental efficiency were accompanied by a significant increase in the interest taken in everyday activities, and suggest that the drug might be helpful in treating the early stages of primary degenerative dementia.
Three antidepressants (amitriptyline, dothiepin, fluoxetine), with and without alcohol, compared with placebo on tests of psychomotor ability related to car driving
Authors: Hindmarch Ian
Published: December 2004

Eight female volunteers received acute doses of amitriptyline 50 mg (AMI), dothiepin 50 mg (DOT), fluoxetine 40 mg (FLU) or placebo both with and without a ‘social’ dose of alcohol (ALC) equivalent to 0·5 g/kg body weight absolute alcohol. Performance on a variety of tests of psychomotor ability and cognitive function (critical flicker fusion, choice reaction time, tracking, Maddox Wing and simulated car steering) were performed at 1·5 and 4 hours following treatment. AMI and DOT both with and without ALC impaired performance on a range of tests at either or both 1·5 and 4 hours, although the effects of AMI and AMI + ALC were more widespread and severe than those found with either DOT or DOT + ALC. FLU and FLU + ALC showed no evidence of impairment on any test at either the 1·5 or the 4 hours assessments. The results suggest that there are differences between the experimental substances, at the doses used, in their intrinsic potential for impairing aspects of psychomotor performance and cognitive function.
A ‘levels of processing’ study of the effects of benzodiazepines on human memory
Authors: Curran H. V. , Schiwy W. , Eves F. , Shine P. , Lader M.
Published: December 2004

A study was designed to test whether anterograde impairments of memory caused by benzodiazepines are dependent on the depth at which information is processed. The effects of two dose levels of two benzodiazepines (lorazepam 1, 2 mg; oxazepam 15, 30 mg) and a placebo were compared using a double‐blind, independent group design with 45 healthy, human volunteers. Subjects given benzodiazepines were slower in processing semantic information than subjects given placebo. The two benzodiazepines caused dose‐related impairments in retention in recognition testing, but these impairments did not depend on the level at which information had been initially processed. It was concluded that the levels of processing framework is inappropriate for conceptualizing the amnesic properties of benzodiazepines.
An investigation of the range of cognitive impairments induced by scopolamine 0·6 mg s.c
Authors: Wesnes K. , Simpson P. , Kidd A.
Published: December 2004

The present study was conducted to determine the degree to which impairments in attention accompany the memory deficits produced by scopolamine. Eighteen healthy young volunteers received scopolamine 0·6 mg subcutaneously on three experimental sessions and placebo on three others. On each session, prior to, and 60 min after injection, the subjects underwent an automated computerized battery of 11 cognitive tasks. The study was run double‐blind and the order of treatment conditions over successive visits was counterbalanced between subjects. Scopolamine produced marked and significant decrements on all major aspects of performance from the battery. The drug lowered the efficiency of the detection and processing of information in tests of visual vigilance, rapid information processing, choice reaction, letter cancellation and logical reasoning. These effects were accompanied by a lowering of critical flicker‐fusion frequency and subjective alertness. Memory was also impaired on tests of immediate recall, delayed recall, recognition and memory scanning. These findings confirm and extend previous work, demonstrating that scopolamine impairs the selection and evaluation of environmental information, as well as reducing the likelihood of information being subsequently recalled or recognized. Whether the former effects contribute to the latter is not known, but this must be considered a possibility. This potential role of processing deficits in memory loss associated with cholinergic blockade is briefly considered in relation to the cholinergic hypothesis of geriatric memory loss.
The effect of clonidine and bright light on plasma melatonin
Authors: Grasby P. M. , Cowen P. J.
Published: December 2004

We studied the effect of the α2‐adrenoceptor agonist, clonidine, and bright artificial light (>2500 lux) on the nocturnal increase in plasma melatonin in normal subjects. Clonidine (1.5 μg/kg, intravenously) was without effect on plasma melatonin concentration. In contrast, bright light treatment abolished the increase in night‐time melatonin. Bright light is a simple and effective means of altering melatonin secretion in humans.
Hypotension and bradycardia induced by amitriptyline in healthy volunteers
Authors: Curry Stephen H. , Devane C. Lindsay , Wolfe M. Michael
Published: December 2004

Seventeen healthy volunters in three groups received no treatment, or 25 or 50 mg doses of amitriptyline. Maximal measured concentrations of amitriptyline occurred at 4 h post‐dosage. There was a dose‐dependent change in performance of a digit symbol substitution test. Visual analogue scales measuring drowsiness, speed of thinking, and lethargy were sensitive to the drug. The low dose induced no blood pressure changes, but tachycardia occurred. The higher dose induced hypotension with bradycardia, a hitherto undocumented reaction to the drug.
A double‐blind trial of evening primrose oil in the premenstrual syndrome: Nervous symptom subgroup
Authors: Callender Kay , McGregor Molly , Kirk Peter , Thomas Christopher S.
Published: December 2004

Forty‐five women were referred to the premenstrual syndrome (PMS) clinic by their general practitioners over a 2‐year period; 24 were included in the study. For 2 months they attended the clinic weekly, where they completed a menstrual distress questionnaire and self‐rating scales relating to depression and anxiety. They also kept a daily record of their symptoms. After this observation period the presence of ‘nervous symptoms’ limited to the premenstrual phase of the menstrual cycle was found in only 12 subjects. These women were randomly allocated to receive either Efamol in combination with Efavit or placebo for 2 months. The following 2‐month washout period was succeeded by a crossover to the other treatment regimen. Ten women completed the trial. The results showed that the depression and anxiety scores improved during the medication months, but that there was no difference between active therapy and placebo.
The benefits and risks of antidepressant drugs
Authors: Pinder R. M.
Published: December 2004

Antidepressant drugs have unequivocally altered the short‐term outcome of depressive illness and reduced considerably the risk of morbidity. Their influence upon the chronic course of depression or upon the excess mortality associated with depressive illness is less easy to quantify. Nevertheless, the benefits of effectively treating depression far outweigh the considerable risks of leaving depressed patients inadequately, inappropriately or untreated. Most antidepressants currently available have broadly equal efficacy, although some drugs may be more appropriate in certain types of patient, when particular symptoms are prominent or when a particular side‐effect is undesirable.

Antidepressants vary in their side‐effect profiles, and the newer non‐tricyclic drugs appear to offer a reduced risk of anticholinergic and cardiovascular effects. All of the newer drugs carry additional adverse effects, however, leading in the cases of zimeldine and nomifensin to withdrawal from the market and with mianserin to controls on prescription. Analysis of overdosage data indicates that the greatest risk of any antidepressant is fatality upon overdosage, the numbers of which far exceed fatalities from adverse effects. It is suggested that any assessment of the overall benefitsand risks of antidepressant drugs should include not only risks at therapeutic dosage but also the dangers of overdosage.
The effects of quazepam, triazolam, flunitrazepam and placebo, alone and in combination with ethanol, on day‐time sleep, memory, mood and performance
Authors: Wickstrøm Egil , Godtlibsen Ole Birger
Published: December 2004

Day‐time sleep and residual effects of quazepam 15 mg, triazolam 0·25 mg, flunitrazepam 1 mg, and placebo, alone and in combination with ethanol, were studied using a randomized, double‐blind, crossover, single‐dose design. Eight healthy volunteers, four male and four female, aged 19–24 years, received each medication in the morning after a ‘normal’ sleep at home the preceding night.

Quazepam and triazolam decreased the sleep onset when compared to placebo. The combination with ethanol did not change these findings. Quazepam and placebo showed less residual effects than triazolam and flunitrazepam at 4 hours after drug intake: in combination with ethanol at 4 and 6 hours. No significant differences in mood were found between the different ‘treatments’, except with regard to alertness for quazepam and placebo compared to flunitrazepam, alone and in combination with ethanol, all at 4 hours.

The combination drug/ethanol showed an increase in Cmax of the former and a delay in Tmax when compared to drug alone. The study indicated few clinically useful correlations between clinical effect and plasma concentration.
Pharmacodynamic and pharmacokinetic comparison of two formulations of lorazepam and placebo
Authors: Abrams S. M. L. , Harry T. V. A. , Hedges A. , Murray G. A. , Turner P.
Published: December 2004

Nine healthy male volunteers took part in a comparison of the pharmacokinetic profiles and effects on psychomotor performance and memory following single dosing with an experimental sustained release (SR) and a conventional release (CR) formulation of lorazepam. There was evidence of a sustained release profile for the SR formulation which had a later tmax (median 8 h) and significantly lower peak serum concentration (mean 12·1 ng ml−1) compared with CR lorazepam (2 h and 21.8 ng ml−1 respectively). The effect of SR lorazepam on pharmacodynamic variables occurred later and was less intense than with CR lorazepam. Good correlations were obtained between most of the pharmacodynamic parameters measured and the logarithm of the serum concentration for both formulations, with the exception of the choice reaction time test for SR lorazepam. However, both formulations produced a similar degree of impairment of 24h recall.
Convulsant actions of the anxiolytic buspirone in combination with antidepressants
Authors: File Sandra E.
Published: December 2004

The anxiolytic, buspirone, was given to rats in combination with four antidepressants: clomipramine (3–30 mg/g), desipramine (5–10 mg/kg), maprotiline (5–15 mg/kg) and mianserin (10–15 mg/kg). Even 2 mg/kg buspirone caused a significant incidence of myoclonic seizures, when combined with clomipramine (30 mg/kg), desipramine (5–10 mg/kg) and mianserin (15 mg/kg). Higher doses of buspirone caused seizures when combined with all doses of the four antidepressants tested. The only antidepressant to cause myoclonus on its own was maprotiline (10 and 15 mg/kg). The university of the incidence of myoclonus precluded any conclusions about the underlying mechnaism. However, whilst it is difficult to draw cross‐species conclusions, our results would caution against the clinical use of buspirone in combination with antidepressants.
Neuropsychiatric aspects of sedative drug withdrawal
Authors: Duncan John
Published: December 2004

The withdrawal syndromes after discontinuance of alcohol, barbiturates, benzodiazepines and other sedative drugs, such as chloral and paraldehyde, are all similar. The severity of a withdrawal reaction is largely determined by the daily dose, the duration of administration and the rate of fall of the drug levels after withdrawal, as well as the propensity of the individual patient. The time course of a withdrawal reaction is determined by the drug's clearance. Alcohol has a half‐life of a few hours; withdrawal symptoms may develop within 6–8 hours of abstinence and convulsions in 12–48 hours. After discontinuance of short‐ or medium‐acting barbiturates (half‐life 8–40 hours) symptoms may develop in 1–3 days, followed by convulsions and delirium after 3–8 days. Symptoms and seizures may develop in the 1–10 days after withdrawal of benezodiazepines.

In patients with no prior history of epilepsy the types of seizures most commonly induced by drug withdrawal are generalized convulsions, but partial seizures are not uncommon if there is a focal cerebral lesion, or a previous history of partial seizures. Paroxysmal activity and photosensitivity may occur after barbiturate withdrawal in non‐epileptics, more commonly in severe withdrawal reactions. Similar EEG changes may be seen after alcohol and benzodiazepine withdrawal, but photosensitivity does not appear to have been shown to be a feature of the benzodiazepine withdrawal syndrome.
Heart rate response to standing as an index of adaptation to imipramine during treatment of panic disorder
Authors: Middleton H. C. , Nutt D. J.
Published: December 2004

The heart rate and blood pressure response to standing in eight patients receiving imipramine treatment for panic disorder were compared with the same measures in eight normal subjects after a single large dose. Despite higher plasma drug levels, patients on long‐term medication had a less abnormal orthostatic response than volunteers. This suggests that the heart rate response to standing could be a useful index of the neuropharmacological adaptation known to occur during administration of therapeutic doses of tricyclic antidepressant.
Absence of acute stimulant effects after intravenous thyrotropin‐releasing hormone (TRH) in man: Comparison to d‐amphetamine
Authors: Little Karley Y. , Garbutt James C. , Mayo James P.
Published: December 2004

Thyrotropin‐releasing hormone (TRH) has been reported to have behavioural effects in man. The current study compared TRH to d‐amphetamine and placebo in normal humans. While a number of d‐Amp effects were noted, TRH was not significantly different from placebo.
Aspects of alpha‐2‐adrenoceptor function in normal volunteers
Authors: Nutt David J. , Glue Paul
Published: December 2004

An intravenous infusion of clonidine (1.5 m̈g/kg) was given to 22 healthy male volunteers to establish normal hormonal biochemical, cardiovascular and psychological responses. Control data were provided by 12 of these subjects who had additional saline infusions, and repeat clonidine infusions were carried out in six subjects to assess test–retest reliability. Clonidine infusion appears to be a safe, reproducible and acceptable means of assessing alpha‐2‐adrenoceptor function in man.
Effects of a subanaesthetic concentration of nitrous oxide on memory and subjective experience: Influence of assessment procedures and types of stimuli
Authors: Block Robert I. , Ghoneim M. M. , Hinrichs James V. , Kumar Viney , Pathak Dhirendra
Published: December 2004

Subjects (16 men and 16 women) breathing 30 per cent nitrous oxide in oxygen, or 100 per cent oxygen, were tested to see if the effects of nitrous oxide on memory varied with different types of auditory stimuli and memory‐testing procedures. The drug produced substantial memory impairments. These impairments were milder in forced‐choice recognition than in yes/no recognition and for certain stimuli (first names of each subject's close relatives), but were not influenced by several other variations in test procedures and stimuli. Additional assessments indicated that nitrous oxide produced numerous subjective effects including some that are characteristic of psychedelic drugs. Subjective rating scales of the kind frequently used in drug studies revealed sedation but not the other mood effects.
Causes, effects and treatment of long‐term benzodiazepine use: A review of psychological perspectives
Authors: Golombok Susan
Published: December 2004

Psychological mechanisms underlying addictive behaviour are described with particular reference to the role of learning and cognition in long‐term benzodiazepine use. The effects of long‐term tranquillizer use on cognitive functioning are then discussed, and it is suggested that the long‐term use of benzodiazepines is associated with impairment in two areas of cognitive functioning; visual‐spatial ability and the ability to sustain attention on a repetitive task under time pressure. Psychological approaches to the management of long‐term benzodiazepine users have focused on tailoring cognitive and behavioural therapeutic techniques to the needs of tranquillizer‐dependent patients. A follow‐up study of patients treated for benzodiazepine dependence is described. It is argued that a gradual withdrawal regimen alone is inadequate for permanent withdrawal for many patients, and that psychological adjuncts should be included in treatment to provide patients with alternative coping strategies.
Saturation analysis of specific 11C Ro 15‐1788 binding to the human neocortex using positron emission tomography
Authors: Persson Anders , Pauli Stefan , Halldin Christer , Stone‐Elander Sharon , Farde Lars , Sjögren Irene , Sedvall Göran
Published: December 2004

The 11C‐labelled benzodiazepine antagonist Ro 15–1788 (flumazenil) and positron emission tomography (PET) were used to determine quantitative characteristics of benzodiazepine receptor binding in the neocortex of healthy young men. Saturating doses of unlabelled flumazenil administered i.v., before or together with the ligand‐reduced 11C‐flumazenil accumulation in the neocortex by about 90 per cent. Saturating doses of unlabelled flumazenil had little effect on the accumulation of radioactivity in the benzodiazepine receptor‐poor regions such as pons or white matter. By giving graded doses of unlabelled flumazenil together with the tracer, saturation isotherms were obtained allowing the calculation of receptor density (Bmax) and equilibrium dissociation constant (Kd) values on the basis of certain assumptions Bmax values were in the order of 90 pmol/g and Kd values in the order of 10 nM in the neocortex. Scatchard and Hill plots of the radioactivity data indicated that 11C‐flumazenil binds to saturable sites of a homogeneous population. The data indicate that intravenous doses of 1 or 2 mg flumazenil result in a benzodiazepine receptor occupancy of about 50 per cent. The method described should be useful for studying regional differences in benzodiazepine receptor characteristics in the living human brain in healthy subjects and neuropsychiatric disorders, and also in relation to treatment with drugs interacting with benzodiazepine receptors.
The dose effects of zopiclone
Authors: Lamphere James K. , Roehrs Timothy A. , Zorick Frank J. , Koshorek Gail , Roth Thomas
Published: December 2004

The dose effects of zopiclone on sleep were studied in 12 subjects. Subjects who complained of insomnia and had their complaint verified by nocturnal polysomnography were included in the study. Four consecutive nights of adaptation and screening, while on placebo, were followed by six 3‐night drug administration periods separated by a 4‐day placebo washout period spent at home. Each of the subjects received placebo, 2·5, 5·0, 7·5, 10·0 or 15·0 mg of zopiclone administered in a double‐blind, randomized, six‐way Latin square design. Zopiclone at all doses significantly increased total sleep time and decreased latencies to sleep compared to placebo dose. Dose differences were found for total sleep time and wake during sleep with 5·0 mg and larger doses differing from 2·5 mg. No further improvement was produced by doses greater than 5·0 mg. Sleep staging effects changed in a dose‐dependent fashion with the 7·5 mg and higher doses significantly different from both placebo and the 2·5 mg dose. In general, hypnotic effects leveled off at the 5 mg dose while sleep stage effects increased with higher doses.
Clinical efficacy of 1‐desamino‐8‐d‐arginine‐vasopressin (DDAVP) in short‐term recovery from minor head injury
Authors: Filipová M. , Jung M. , Filip V. , Krejčová H.
Published: December 2004

The purpose of the study was to investigate whether 1‐desamino‐8‐D‐arginine‐vasopressin (DDAVP) has a positive effect on mental performance in patients recovering from minor head injury. Seventeen inpatients with simple closed‐head injury were included in the trial within 16–40 h after the accicent. DDAVP (Adiuretin SPOFA 10 m̈g) b.i.d. or placebo were administered intranasally for 4 days under double‐blind conditions. The test battery, consisting of several tests of memory and information processing, was administered at pretreatment and at the end of the trial. All patients completed the protocol, nine in the DDAVP group and eight in the placebo group. No adverse reactions to treatment were observed. In the first and second series of PASAT (an information processing test) and in the Story Memory (a test of verbal logical memory) DDAVP was significantly (p<0·05) superior to placebo according to t‐tests and/or ANCOVA with age as covariate. The results indicate a positive influence of DDAVP on information processing and short‐term verbal logical memory during recovery from minor head injury.
An open study of buspirone in octogenarians with anxiety
Authors: Levine Sidney , Napoliello Michael J. , Domantay Antonio G.
Published: December 2004

In this study buspirone demonstrated efficacy and safety in the treatment of anxiety in elderly patients age 80 years or older. The results are consistent with data from earlier clinical and pharmacokinetic studies in elderly patients 60 years and older.
A pilot study of verapamil in the treatment of tardive dyskinesia
Authors: Dinan Timothy G. , Capstick Claire
Published: December 2004

Six patients with severe and stable tardive dyskinesia were treated with verapamil, a calcium channel blocker, in doses ranging from 240 to 400 mg/day. Weekly assessments were made using the Simpson tardive dyskinesia rating scale. Neuroleptic medication was held constant during the 3‐month baseline assessment and during the month of treatment with verapamil. Four of the six patients showed a dramatic response to treatment and a fifth showed a slight improvement. The four good responders were younger and had the tardive dyskinesia for a shorter period of time.
Benzodiazepines and appetite: Recent pre‐clinical advances and their clinical implications
Authors: Cooper Steven J.
Published: December 2004

Since their introduction in the early 1960s it has been known that benzodiazepines potently increase food intake in many animal species, including higher primates. Behavioural and pharmacological evidence shows that this hyperphagic effect of benzodiazepines is not secondary to their anxiolytic properties, and can also be dissociated from sedative and muscle‐relaxant effects. The hyperphagic response appears to be due to a direct effect on appetite mechanisms, and certainly arises from interactions of drugs with specific benzodiazepines recognition sites in the brain. The discovery of so‐called ‘inverse agonists’, which bind to benzodiazepine sites, has led to experiments which show that they reduce food consumption and can block benzodiazepine‐induced hyperphagia. The most recent research in this area shows that benzodiazepines enhance the hedonic quality of taste stimuli, and indicates that this may determine their effects on food preferences and food consumption. This evidence is reviewed in this article. Attention is also drawn to recent experimental work in patients with eating disorders; anorexia nervosa and bulimia. Both groups show heightened taste responsiveness to sweet, palatable taste. Further study of benzodiazepine effects on appetite should throw new light on neurochemical determinants of taste palatability. Inverse agonists acting at benzodiazepine receptors may provide examples of drugs which could be used to attenuate taste responsiveness to highly palatable foods.
The prescription of antidepressants in general practice: I a critical review
Authors: Thompson C. , Thompson C. M.
Published: December 2004

This review critically examines the literature which is available on the way in which general practitioners use antidepressants, the kind of depressed patients who they choose to treat, and the trials of antidepressants which have specifically been carried out in general practice. General practitioners tend to use a ‘low‐dose strategy’ of prescribing tricylics (75 mgs or less per day), which are the most commonly used antidepressants.

While this is a subtherapeutic dose in psychiatric hospital patients there is evidence that GP's patients are less serverely depressed, and the low‐dose strategy might be effective in such cases. A review of trials in general practice revealed only one study capable of addressing this question, which suggested a lack of efficacy of the low‐dose strategy.
Ethanol interactions with serotonin uptake selective and non‐selective antidepressants: Fluoxetine and amitriptyline
Authors: Shaw Carolyn A. , Sullivan John T. , Kadlec Karen E. , Kaplan Howard L. , Naranjo Claudio A. , Sellers Edward M.
Published: December 2004

Fluoxetine, unlike amitriptyline, selectively blocks serotonin uptake. The interactions of steady state levels of fluoxetine with ethanol and of amitriptyline with ethanol were measured in a double‐blind, chronic dose, randomized study. Sixteen healthy men, ages 21 to 28 years, were tested with placebo and ethanol (dosed to maintain blood ethanol concentration of 17–22 mM) and placebo and juice on two separate days. For 14 nights, 8 subjects took fluoxetine 40 mg, 8 took amitriptyline 50 mg, and all were re‐tested with ethanol and juice as before. Ethanol had no effect on inhibition of serotonin uptake or on pharmacokinetics of fluoxetine or amitriptyline. The deleterious effects of ethanol on memory, manual tracking, body sway, intoxication and sedation (p<0·05) were not modified by either fluoxetine or amitriptyline. This study design, which is sensitive enough to detect ethanol effects, suggests that ethanol dose not interact importantly with clinically relevant doses of fluoxetine or low doses of amitriptyline administered chronically.
Remoxipride in the treatment of coexistent schizophrenia and parkinson's disease
Authors: Cooper Stephen J. , Doherty Michael M.
Published: December 2004

Schizophrenia and Parkinson's Disease occasionally co‐exist in a patient. This poses a therapeutic problem. We report a case in whom remoxipride was useful for this situation.
Acute hypertensive episode induced by sulpiride – a case report
Authors: Mayer Robert D. , Montgomery Stuart A.
Published: December 2004

A case study is described of a hypertensive episode associated with sulpiride which is a selective antagonist of cerebral dopamine receptors. The association with sulpiride was confirmed by withdrawal and rechallenge with the drug.
Effects of prenatal neuroleptic drug exposure on motor performance in children
Authors: Platt Jane E. , Friedhoff Arnold J. , Broman Sarah H. , Bond Ronald , Laska Eugene , Lin Shang P.
Published: December 2004

In a previous study we showed that prenatal neuroleptic drug exposure has postnatal effects on children's growth (Platt et al., 1988). In the present study the effect of prenatal exposure to neuroleptic drugs on motor performance at birth, 8 months, 4 years and 7 years of age was examined in children of psychiatrically normal parents, and of parents with a history of psychiatric treatment, using‐data from the Collaborative Perinatal Project of the National Institute of Neurological Diseases, Communicative Disorders and Stroke. The majority of the analyses were done using multiple logistic regression to control for possible confounding factors and to derive risk ratios. Some negative effects on motor behaviour were present in all groups at birth, most noticeably in the group of children who had been exposed to dopamine (DA)‐depleting drugs. Negative effects were less prevalent at later ages, but were still present. The results are discussed in terms of possible mechanisms and methodological limitations.
Pharmacotherapy in personality disorder
Authors: Nicholson Simon
Published: December 2004

Personality disorders pose a major therapeutic challenge in psychiatry. However, a substantial body of research suggests that various pharmacological agents, especially low‐dose neuroleptics, may be useful against affective, cognitive and behavioural symptoms occurring in these patients. It is proposed that a trial of drug treatment, in accordance with the principles outlined in the literature, is a valid strategy in this difficult area.
Acute effects of hydroxyzine on nocturnal sleep and sleep tendency the following day: A C‐EEG study
Authors: Alford C. , Rombaut N. , Jones J. , Foley S. , Idzikowski C. , Hindmarch I.
Published: December 2004

The acute hypnotic effects of hydroxyzine 25 mg and 50 mg nocte, were examined in six male and six female volunteers. Continuous electrophysiological measures (C‐EEG) were taken to assess both nocturnal sleep and sleep tendency the following day. Both doses produced significant reductions in sleep onset latency and decreases in waking during sleep; reciprocal increases in sleep duration were also seen. Female subjects demonstrated a greater hypnotic response, including a dose‐dependent decrease in sleep onset latency. Increases in sleep duration following both doses were significant for the female group alone. C‐EEG measures of increased drowsiness the following day failed to achieve significance; although the largest effects on daytime sleepiness, including dose‐dependent increases, were again seen with the female subject group and corresponded with subjective ratings. These results demonstrate the hypnotic efficacy of hydroxyzine whilst failing to detect significant C‐EEG hangover effects. However, variability in response to antihistamines, registered here as differences between the sexes, requires further consideration.
Effects of nitrous oxide on memory for instructions in dental patients
Authors: File S. E. , Balakrishnan J. , Murray A. , Harris A. , Skelly A. M.
Published: December 2004

Outpatients attending for conservative dental treatment were presented with eight instructions which they were asked to remember. The instructions were either written or spoken, and were in a positive or negative form. Patients treated with nitrous oxide remembered fewer instructions than those treated with local analgesia alone, and this effect of nitrous oxide was particularly marked for written instructions. Patients receiving local analgesia alone were more likely to remember positive than negative instructions in their original syntactical form, but this bias was not evident in the nitrous oxide group. In a second experiment both normal and dentally phobic patients were read dental and general instructions both before and during inhalation of 30 per cent nitrous oxide. Both groups showed a nitrous oxide‐induced reduction in partially recalled instructions. There was interesting evidence for a different attentional bias in our two patient groups. The normal group remembered more general than dental instructions, whereas the phobic group showed the opposite pattern, yielding a significant patient group × type of instruction interaction.
Ligand metabolites in plasma during PET‐studies with the 11C‐labelled dopamine antagonists, raclopride, SCH 23390 and N‐methylspiroperidol
Authors: Swahn Carl‐Gunnar , Farde Lars , Halldin Christer , Sedvall Göoran
Published: December 2004

The 11C‐labelled radioligands raclopride, SCH 23390 and N‐methyl‐spiroperidol are well established for examination of central dopamine receptors by positron emission tomography (PET).

Thin layer chromatography was used to examine the composition of radioactivity in plasma after intravenous injection of any of these three ligands into human subjects. For all three ligands there was a considerable metabolism during the time of a PET‐experiment but to a different degree. Forty‐two minutes after injection (11C)raclopride was unchanged to 76 per cent, (11C)N‐methylspiroperidol to 57 per cent and (11C) SCH 23390 only to 13 per cent.

A time curve for ligand metabolism is necessary for compartmental analysis with an arterial input function. The considerable ligand metabolism demonstrated shortly after i.v. injection motivates further the identification of main metabolites to evaluate if they pass the blood‐brain barrier and bind to the receptors.
Clomipramine/bentazepam combination in the treatment of major depressive disorders
Authors: Ordóñez A. Calcedo , Arosamene X. , Pérez F. J. Otero , Herrero C. Hernández , García A. , Moral L. , Baeza F. , Benitez J. Fernández , Velasco J. , Garrido J.
Published: December 2004

Eighty‐three patients were recruited in a multicentre study concerning the usefulness of benzodiazepines (BZ) in major depressive disorders, diagnosed according to the DSM‐III‐R criteria. After 1 week wash‐out, patients were randomized to clomipramine (CLMP) or CLMP plus bentazepam (BTZ) treatments (47 and 36 patients respectively). It was necessary to add hypnotics, usually a BZ, in 11 patients in the CLMP group and in one patient in the CLMP + BTZ group. The clinical improvement was faster in the group treated with CLMP + BTZ and, at the end of 6 weeks of treatment, the mean score in Hamilton Anxiety Scale (HAS) was lower than the one found in the group treated with CLMP. There were no significant differences found in Hamilton Depression Scale (HDS) between the groups. The side‐effects observed were those due to CLMP, and only drowsiness was more frequent in the CLMP+BTZ group. However, the CLMP+BTZ combination was equally or better tolerated by patients than by those treated with CLMP alone. Similar results were found in hospitalized as well as in outpatients. The tricyclic antidepressant (TCA)/BZ association showed better results than TCA alone, producing a symptomatic improvement extensive to the anxious components of depression.
Reliability and sensitivity of performance tests in human psychopharmacology. A commentary on the articles by parrott (1991), human psychopharmacology, 6, 1–9, 91–98, 197–207
Authors: Tiplady Brian
Published: December 2004

This commentary argues that the conventional assessment of the reliability of psychological tests may be inappropriate in psychopharmacology. The conventional approach depends upon the assessment of differences between individuals rather than changes within individuals. It thus favours measures of trait, while those required for investigating drug‐induced changes are measures of state. The sensitivity of a measure to change is a more useful criterion for inclusion in a test battery for the investigation of the effects of drugs.
The effect of caffeine use on a visual information processing task
Authors: Loke Wing Hong , Goh Winston D.
Published: December 2004

Past caffeine studies have shown that differences in task performance may be due to differences in habitual caffeine consumption levels of individuals. No study has yet investigated this caffeine user effect alone without confounding it with the administration of caffeine. The present study used a visual search/detection task to test whether high caffeine users have an enhanced resource capacity and therefore show higher baseline performance than low and moderate caffeine users. A three‐way interaction between caffeine user (low, moderate, and high caffeine user), automaticity (automatic and non‐automatic), and task difficulty (low and high) was predicted, with user effect significant for the non‐automatic portion of the task. The three‐way interaction was not significant, suggesting that user effect is not dependent on resource capacity. Several interpretations, based on theoretical, empirical, methodological, and statistical viewpoints, are discussed as to the non‐significant caffeine user effect.
Effects of scopolamine on immediate postural changes in heart rate and R—R variance in humans
Authors: Yeragani Vikram K. , Pohl Robert , Balon Richard , Ramesh C. , Berchou Richard
Published: December 2004

To examine the anticholinergic effects of scopolamine, postural tests were performed in nine healthy male volunteers after they received intravenous infusions of 0.2mg of scopolamine, 0.4 mg of glycopyrrolate, or placebo on separate days under double‐blind randomized conditions. Compared to the placebo and glycopyrrolate conditions, scopolamine produced a significantly exaggerated HR response to standing from supine posture. Scopolamine also produced a significant increase in R‐R variance during supine deep breathing and standing conditions as compared to glycopyrrolate and placebo conditions. At the same time, scopolamine also produced a significant dry mouth. These findings suggest that the effects of scopolamine in low doses on the above cardiac variables are vagomimetic.
Treatment of neuroleptic malignant syndrome with levodopa
Authors: Otani K. , Mihara K. , Kondo T. , Okada M. , Kaneko S. , Fukushima Y.
Published: December 2004

Seven consecutive episodes of neuroleptic malignant syndrome in five cases were treated with 50–600 mg/day (mean 342 mg/day) of levodopa. In four episodes active pharmacological treatment was initiated with levodopa, while in the remaining three episodes it was introduced because of poor therapeutic response to dantrolene. Levodopa treatment brought complete recoveries in six out of the seven episodes. In the remaining episode, levodopa appeared to be at least partially effective, although it had to be discontinued prematurely because of vomiting. As complications of levodopa, psychotic symptoms developed in one case. The present report suggests that levodopa can be a first choice in the pharmacological treatment of neuroleptic malignant syndrome, although attention should be paid to the development of vomiting and psychotic symptoms as possible complications. It also supports the view that central hypodopaminergic states are the underlying pathophysiology in this syndrome.