Search

Background: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment., Subjects and Methods: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures., Results: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001)., Conclusion: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

The aim of the present study was to perform a critical reflection about intervention options for bruxism reduction in children and adolescents. Search was conducted based on the PICO-structured question: "What are the intervention options to reduce bruxism in children/adolescents?". No language, year, or study design restrictions were imposed. Studies reporting interventions to reduce bruxism in children (< 10) and adolescents (10 to 19 years old) were included. Reviews and letters to editors were not included. From 2723 records, 17 papers were included. Included studies were primarily randomized clinical trials performed in Brazil (35.3%) and using different criteria for the diagnosis of bruxism. Reduction in self-reported bruxism and headaches associated with bruxism were observed in studies that used medications (hydroxyzine/trazodone/flurazepam), occlusal splints, orthodontic interventions, and psychological and physical therapy interventions. Reduction in Rhythmic Masticatory Muscle Activity was observed with the use of the occlusal splint and in orthodontic interventions. Alternative treatments (medicinal extracts such as Melissa officinalis-L) have shown inconclusive results.Conclusions: Several intervention options are available to inhibit or reduce bruxism activity. The respective indication, contraindications, and side effects of each treatment option must be assessed individually and carefully, taking into account that bruxism is not considered a disorder in otherwise healthy individuals.What is known• Biological and psychological factors have been strongly correlated to the development of bruxism• Bruxism prevalence ranging from 6 to 50% in childrenWhat is new• Reduction in self-reported bruxism and headaches associated with bruxism were observed in studies that used medication (Hydroxyzine/ Trazodone/ Flurazepam), occlusal splints, orthodontic interventions, psychological, and physical therapy interventions• A reduction in Rhythmic Masticatory Muscle Activity was observed with the use of the occlusal splint and orthodontic interventions. Alternative treatments (medicinal extracts such as Melissa officinalis L) show inconclusive results in respect of the reduction in bruxism.

Folie à deux is a relatively rare mental disorder first described in France in 1877 by Lasègue and Falret. However, folie à deux is still a matter of study and debate today as it remains a challenge for psychiatrists. The aim of our work is to report a clinical case of folie à deux, subtype A of Gralnick, between an inducer daughter and an induced mother who lived quite socially isolated and had a strong and close relationship. In the clinical case presented, folie à deux was easily diagnosed but its treatment proved to be a higher challenge. The main diagnosis of the inducer patient was also quite interesting. Many years after it was first described, folie à deux is still an interesting and challenging disorder to psychiatrists, especially concerning its pathophysiology and treatment.

Knock-in mice were constructed with mutations in the α1 (H(270), A(277)) and α2 (H(270), A(277)) subunits of the GABAA receptor, which resulted in receptors that lacked modulation by ethanol but retained normal responses to GABA in vitro. A key question is whether these mutant receptors also function normally in vivo. Perturbation of brain function was evaluated by gene expression profiling in the cerebral cortex and by behavioral pharmacology experiments with GABAergic drugs. Analysis of individual transcripts found only six transcripts that were changed in α1 knock-in mice and three in the α2 mutants (p<0.05, corrected for multiple comparisons). Two transcripts that are sensitive to neuronal activity, Arc and Fos, increased about 250% in the α2 mutants, and about 50% in the α1 mutants. Behavioral effects (loss of righting reflex, rotarod) of flurazepam and pentobarbital were not different between α2 mutants and wild-type, but they were enhanced for α1 knock-in mice. These results indicate that introduction of these mutations in the α2 subunit of the GABAA receptor does not produce marked perturbation of brain function, as measured by gene expression and GABAergic behavioral responses, but the same mutations in the α1 subunit produce more pronounced changes, especially in GABAergic function., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: Benzodiazepines (BZDs) have been reported to cause negative impacts on body stability and cognitive functions, which in turn could result in lethal incidents, including falls, especially in the elderly. This fact notwithstanding, no systematic trial has evaluated the feasibility and benefits of discontinuing BZD-derivative hypnotics in this population, which was addressed in this study., Methods: In this 8-week open-label study, subjects aged ≥ 60 living in a nursing home who received BZD as a hypnotic were recruited. The BZD dose was tapered off over 3 weeks. The following assessments were performed 12 h post-dose at baseline and at endpoint: the Clinical Stabilometric Platform (CSP), the Critical Flicker Fusion Test (CFF), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Leeds Sleep Evaluation Questionnaire (LSEQ)., Results: Thirty subjects were enrolled (mean ± SD age = 79.1 ± 8.9 years, mean ± SD flurazepam equivalent BZD dose = 19.5 ± 10.9 mg/day). Psychiatric diagnoses (DSM-IV) of subjects were as follows: schizophrenia (n = 12), primary insomnia (n = 9), dementia (n = 7), and bipolar disorder (n = 2). In 26 completers, significant changes were found in a total length and a range of trunk motion with eyes closed. Significant improvements were also observed in the CFF and RBANS immediate memory, language, and attention index scores. Subjective worsening in sleep was not reported in those completers, assessed with the LSEQ., Conclusions: Our results suggest that discontinuation of BZD hypnotics is feasible in a majority of elderly persons and leads to an improvement in the stability of body and a recovery in cognitive functions during the daytime., (Copyright © 2010 John Wiley & Sons, Ltd.)

Many epidemiological studies assess the effects of time-dependent exposures, where both the exposure status and its intensity vary over time. One example that attracts public attention concerns pharmacoepidemiological studies of the adverse effects of medications. The analysis of such studies poses challenges for modeling the impact of complex time-dependent drug exposure, especially given the uncertainty about the way effects cumulate over time and about the etiological relevance of doses taken in different time periods. We present a flexible method for modeling cumulative effects of time-varying exposures, weighted by recency, represented by time-dependent covariates in the Cox proportional hazards model. The function that assigns weights to doses taken in the past is estimated using cubic regression splines. We validated the method in simulations and applied it to re-assess the association between exposure to a psychotropic drug and fall-related injuries in the elderly.

The inbred Balb/c mouse strain was more sensitive than the outbred NIH Swiss mouse to flurazepam's ability to antagonize electrically precipitated seizures. In prior work, a reduction in flurazepam's antiseizure efficacy was not observed 24h after forcing Balb/c mice to swim for up to 10 min in ambient temperature water. Thus, we wondered if a stress-induced reduction would be observed after forcing mice to swim for up to 10 min in cold (6 degrees C) water, a more severe stress. The current data show that 24 h after exposure to this stress, the ability of flurazepam to raise the threshold voltage for the elicitation of tonic hindlimb extension in the Balb/c mouse strain was reduced. The genetically inbred Balb/c mouse strain is emerging as an interesting animal model in which to study interactions of stress and genetic factors that affect endogenous neurotransmission mediated by l-glutamate and GABA at the NMDA and GABA(A) receptor complexes, respectively.

Stress induces changes in the endogenous tone of both GABA and NMDA receptor-mediated neurotransmission in the intact mouse. Because changes are observed 24 h after stress, epigenetically-regulated alterations in gene expression may mediate these effects. In earlier work, sodium butyrate, a centrally-active histone deacetylase inhibitor that promotes gene expression, was shown to modulate the stress-induced reduction of the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically-precipitated seizures. In the current study, we extended this work to look at sodium butyrate's modulatory effect on stress-induced changes in the antiseizure efficacy of flurazepam, a benzodiazepine receptor agonist, in two strains of mice. Epigenetic mechanisms, genetic strain differences and a standard stress interacted to alter flurazepam's antiseizure efficacy. These data support examination and development of epigenetic treatment strategies.

Stevens-Johnson syndrome and toxic epidermal necrolysis are rare, but severe cutaneous reactions. Beside cutaneous manifestations, the syndrome is characterised by constitutional sypmtoms with even lethal consequences. Toxic epidermal necrolysis is usually a drug-hypersensitivity syndrome. More than a hundred drugs were suspected to cause toxic epidermal necrolysis. Although benzodiazepines had been suspected in some cases, flurazepam has not been implicated thus far. The authors report a severe, life threatening case of toxic epidermal necrolysis in a young woman suffering from schizophrenia. The most probable cause was flurazepam, a hypnotic agent of the benzodiazepine class.

Based upon the conception of "circular-type addiction" scientists mark out psychological (alexithimia), psychopathological (anxiety and depressive disorders), neurological (insomnia) and somatic (circulator disturbances) levels in pathogenesis of arterial hypertension. Sleep disorder have been noted to be a key symptom in phenomenology of arterial hypertension therefore it is recommended giving Somnol as an adjuvant remedy for treatment of arterial hypertension.

This investigation compared progressive muscle relaxation plus cognitive distraction (PMR/CD), hypothesized to better improve sleep onset, versus sleep restriction and stimulus control (SR/SC), hypothesized to better improve sleep maintenance, versus a flurazepam (Dalmane) positive contrast condition (MED) and a sleep hygiene education minimal treatment control condition (SHE). Participants with chronic insomnia (N = 53), completed 2 baseline weeks of sleep diaries, and were randomly assigned to a treatment group for 2 more weeks. In the second phase, PMR/CD participants were assigned to 2 weeks of PMR/CD + SR/SC + SHE while SHE participants continued SHE. Results indicated that PMR/CD had greater effect upon sleep onset than SR/SC and SHE, SR/SC had greater effect on sleep maintenance than PMR/CD, and MED was better than the other treatments. In the second phase, the treatment package produced modest additional improvements and SHE performed superior to expectations.

The present randomized, double-blind, placebo and active-drug controlled, crossover study assessed residual sedation after zaleplon 10 mg, flurazepam 30 mg (as an active control), and placebo, taken during a nocturnal awakening in patients with sleep maintenance insomnia. Twenty-two healthy sleep maintenance insomniacs (11 men; mean age, 42 y) received zaleplon, flurazepam, or placebo after an experimental awakening 3.5 hours after bedtime on two consecutive nights in each of three conditions. Residual sedation was measured with sleep latency testing (5 and 6.5 h postdrug), digit symbol substitution, symbol copying, and subjective sleepiness by visual analog scale, each twice each morning. Zaleplon did not differ from placebo on any measure of residual sedation; flurazepam showed significant sedation on all measures. No residual sedative effects were detected 5 or 6.5 hours after ingestion of zaleplon during the middle of the night by sleep maintenance insomniacs.

We have shown previously that the benzodiazepine hypnotic triazolam alters the perception of being awake or asleep in insomniacs, making it more likely that they will report having been asleep when awakened by an electronic tone at various times of the night. In the present study, we examined the question as to whether this is also true for other benzodiazepines as well as for nonbenzodiazepine hypnotics. Ten insomniacs were given placebo, flurazepam 30 mg and zolpidem 10 mg and were awakened at five times during subsequent sleep in a random-sequence repeated-measures study. Across all five awakenings following placebo, insomniacs reported being asleep with a frequency of 30.9%. This rose to 40.4% (ns) and 54.7% (p < 0.03) on flurazepam and zolpidem, respectively. Subjects were also more likely to report having been dreaming during the awakening 5 minutes after "lights out" after receiving zolpidem. A number of polygraphic measures of sleep, including sleep latency, total sleep and sleep efficiency, improved significantly on both drugs, and there was similar improvement in some global measures of quality of sleep. Neither drug altered the subjective sense of duration of time. These findings suggest that drug-induced alterations in the perception of being awake or asleep are not unique to benzodiazepines, but occur with the nonbenzodiazepine zolpidem as well.

In previous studies we have reported that the benzodiazepine hypnotic triazolam and the nonbenzodiazepine zolpidem increase the likelihood that insomniacs will report having been asleep when awakened by an electronic tone of progressive intensity. It has not been known, however, whether this occurs with normal sleepers. In the present study we have administered placebo, flurazepam 30 mg and zolpidem 10 mg to 15 normal sleepers and awakened them with an electronic tone at five points across the night. In contrast to previous reports with insomniacs, both compounds made only modest improvements in sleep. When all time points were combined, subjects reported having been asleep in 40.3, 42.9 and 47.9% of the trials on placebo, flurazepam and zolpidem, respectively (ns). Subjects were accurate in their estimate of total time asleep, and this accuracy was not influenced by the drugs. Similarly, there were no effects on a variety of questions related to dreaming and other cognitive activity during sleep. These results suggest that the effects of these hypnotics, which have been described previously in insomniacs, are not found in normals. Further studies will be necessary to clarify whether such effects in insomniacs are related to the clinical efficacy of hypnotics.

Objectives: To identify the characteristics of patients who present to office-based physicians with complaints of insomnia, the physicians' diagnoses related to these complaints, and the use of prescription sleep medications., Methods: Based on 1989 and 1990 data from the National Ambulatory Medical Care Survey, with 3105 physicians participating (response rate, 74%). Participating physicians recorded data for a total of 81,853 patient visits. Patient characteristics, presenting complaint, diagnosis of condition, and pharmacologic therapy were included., Results: Annually, there are 3.3 million visits to office-based physicians for complaints of insomnia, 65% of which are to primary care specialists. Rates of insomnia visits are somewhat higher for middle-aged (45 to 64 years of age) women, and data for female insomniacs suggest a trend toward diagnoses of depression compared with other (somatic) diagnoses for men. The prescribing of long-acting sleep medications does not differ significantly by physician specialty, but it declines with increasing patient age., Conclusions: Physician visits for insomnia account for only a small proportion of office visits but offer the opportunity for identification of underlying illnesses and for the prevention of associated problems. While some differences in diagnosis are associated with patient characteristics (possibly reflecting a bias in the workup), sleep medications appear to be prescribed appropriately, with a declining rate in the prescribing of long-acting medications for older patients.

Insomnia is commonly encountered in general medical practice, but little is known about how primary care physicians manage this problem. We reviewed medical records describing 536 patient encounters in which either triazolam (Halcion) or flurazepam (Dalmane) was prescribed for outpatient use. Only 12% of the progress notes written by internists or surgeons contained even a remote reference to sleep, whereas 74% of psychiatrist's notes contained at least some sleep symptom documentation. In a multivariate analysis including the number of medical and psychiatric diagnoses, patient age, and physician gender, only the prescriber department was independently associated with the presence of symptom documentation. We also found that 30% of the prescriptions written by internists or surgeons were for inappropriately large quantities of these drugs (180 or more doses) compared with 6% of the prescriptions written by psychiatrists. We conclude that the evaluation of insomnia by nonpsychiatrists is often incomplete and that hypnotic drugs may be inappropriately prescribed by these physicians. Further efforts are needed to improve the management of insomnia by primary care physicians in the outpatient setting.

The "revolution" in pharmacologic treatment of insomnia began in 1970 with the availability of flurazepam, the first of the benzodiazepine hypnotics. Flurazepam largely replaced all other hypnotics during the decade of the 1970s. The second revolution began in the early 1980s as shorter half-life hypnotics, triazolam and temazepam, became available and began to replace flurazepam. The decade of the 1990s will probably see a more balanced pattern of benzodiazepine hypnotic use, as well as use of newer nonbenzodiazepine hypnotics. Among available benzodiazepines, all have the capacity to produce dose- and concentration-dependent sedation, drowsiness, performance impairment, and amnesia. Benzodiazepine-induced amnestic effects are characterized by either impairment of information acquisition, impairment of consolidation and storage, or both. In general, apparent clinical differences among benzodiazepine hypnotics are explained by differences in pharmacokinetic properties of absorption, distribution, elimination, and clearance.

Insomnia is common in the elderly population. Difficulty in initiating and maintaining sleep affects nearly half of all patients over the age of 65, representing an increased prevalence in older versus younger patients. Nocturnal sleep time is decreased, frequent awakenings occur, and daytime napping is common. Age-related changes in sleep physiology correlate with the subjective complaints of disturbed sleep. Multiple etiologies for insomnia in the elderly have been described. Management strategies must include attention to both nonpharmacologic and pharmacologic aspects of care, especially with respect to the altered pharmacokinetics and pharmacodynamics associated with advanced age. Reassessing therapy is essential to promote the end goal of improvement of the elderly patient's quality of life.

Benzodiazepine drugs have been shown to suppress respiratory function in patients with chronic obstructive pulmonary disease (COPD). We designed a placebo-controlled crossover study to compare the effects of a new benzodiazepine, estazolam ('ProSom'), with those of flurazepam ('Dalmane') on cardiopulmonary function in COPD patients. 29 patients completed all treatment phases (estazolam 2 mg, flurazepam 30 mg or placebo). Respiratory and cardiovascular function were assessed in awake patients on days 1 and 5 (acute and cumulative effects). Eight patients were also assessed during sleep in each period. The effects of estazolam and flurazepam on ventilatory response to CO2 and mouth occlusion pressure were no different from those of placebo. However, acute administration of flurazepam lowered tidal volume and increased inspiratory flow. Although no clinical signs of respiratory depression were observed with any long term treatment, flurazepam decreased oxygen saturation and inspiratory time and increased respiratory frequency. Neither drug altered breathing control during sleep. Our results indicate that estazolam 2 mg is equally as safe a hypnotic agent as flurazepam for patients with mild COPD.

Daytime residual drowsiness and psychomotor performance were assessed for two long half-life benzodiazepines, quazepam and flurazepam, in two randomized, parallel, and double-blind studies in insomniacs. Seventeen middle-aged patients took quazepam 15 mg or 30 mg, or flurazepam 30 mg; the 47-night study included 4 placebo baseline nights, 28 consecutive treatment nights, and 15 posttreatment nights. Forty-eight geriatric patients took either flurazepam 15 mg, quazepam 15 mg, or placebo; the 15-night study included 1 placebo baseline night, 7 treatment nights, and 7 posttreatment nights. The Multiple Sleep Latency Test (MSLT), an objective test for measuring daytime sleepiness, and performance tests were administered. In the first study, flurazepam patients were significantly (p less than .05) sleepier after the 7th and 14th treatment nights when compared to baseline, whereas quazepam patients were not. In the second study, flurazepam patients were sleepier at midday (p less than .10) and late afternoon (p less than .05) after 1 treatment week than were quazepam and placebo patients. Performance test results suggested quazepam has a relatively low potential for daytime impairment. Thus, quazepam 15 mg produces less daytime somnolence and fewer psychomotor performance decrements than does flurazepam.

Estazolam is a new benzodiazepine hypnotic agent with an intermediate half-life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double-blind, placebo-controlled, multicenter, 7-night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Findings from a four-city study of the beneficial and adverse effects of hypnotics are reported. The study employed a new volunteer call-in method for monitoring drug effects outside of the clinical setting. Respondents were recruited through newspaper advertisements. They were invited to complete a short telephone interview if, during the past 12 months, they (1) had significant trouble with insomnia or (2) had taken a medication to induce sleep. Comparison groups were flurazepam, temazepam, triazolam, and over-the-counter (OTC) sleep medications. An untreated insomnia group also was included. Results indicate that most users of prescription hypnotics attributed positive effects to their sleep medications and that adverse effects were infrequent. OTC hypnotics were less effective and more likely to produce negative effects. The untreated insomnia group was more symptomatic than any of the medication groups.

A systematic approach to the common complaint of insomnia usually results in a specific clinical diagnosis with clear therapeutic implications. Use of effective treatment strategies tailored to the situation can make treating insomnia a gratifying experience instead of a frustrating one.

Zopiclone (7.5 mg), a cyclopyrrolone derivative with a 6.5 h half-life, and flurazepam (30 mg) were compared to placebo in a randomized double-blind study involving 36 adult patients suffering from insomnia. All previous psychotropic drugs were discontinued 1 week prior to the study. During 4 weeks, 12 patients received zopiclone, 12 flurazepam and the others placebo. Thereafter, all patients received single-blind placebo for 3 nights. Rapidity of sleep onset, sleep duration, frequency of nocturnal awakenings, psychomotor coordination and side-effects were assessed daily with a questionnaire and a symptom checklist. The results of the study suggest that zopiclone 7.5 mg was at least as potent as flurazepam 30 mg in inducing and maintaining sleep. Both drugs maintained their efficacy during the 4 weeks of treatment. However, the two drugs differed in that flurazepam impaired psychomotor coordination whereas zopiclone did not demonstrate daytime protracted effects on psychomotor performance. Upon discontinuation of drug treatment, score values of the different sleep parameters under study returned to the baseline values. Side-effects were mild and consistent with earlier studies.

Four skills performance (psychomotor) tasks, including simple and choice reaction time, divided attention, and vigilance, were given to 99 chronic insomniacs to determine whether the use of midazolam 15 mg, or of flurazepam 15 or 30 mg, compared with placebo would produce next-day impairment throughout a 14-day treatment period. Tests were administered during 2 baseline days and on treatment days 1 and 2 (early interval), 7 (middle interval) and 13 and 14 (late interval). Compared with placebo, performance on all four tasks was impaired by flurazepam 30 mg. The deficits associated with flurazepam 15 mg were roughly half the magnitude of those produced by flurazepam 30 mg, but these changes did not reach statistical significance for single response measures at single time intervals. Midazolam showed no consistent pattern of performance effects; however, for divided attention tracking error, there was a significant decrement. The placebo group showed flat performance curves or improved performance as a result of learning (practice effect).

Blood samples were drawn from each of 99 chronic insomniacs twice during washout (days -20 and -6) and six times during the study (mornings after study nights -1, 1, 2, 7, 13, and 14) to examine the relationship between morning-after drug plasma levels, sleep efficiency, next-day mood, and performance. Patients in the four treatment groups received either flurazepam 30 mg, flurazepam 15 mg, midazolam 15 mg, or placebo. Plasma drug concentrations of N-desalkylflurazepam and midazolam were measured by electron-capture gas chromatography. Values of midazolam during the 14-day study were at or near the sensitivity limit of the assay and were not used in the calculations. Levels of N-desalkylflurazepam increased as expected during the 14 days. Mean level for the high-dose flurazepam group was approximately twice that of the low-dose group. The main consistency in the correlations, which were found on days 13 and 14, was that the high-dose desalkylflurazepam concentrations had a negative correlation with two independent measures of sleep latency. However, otherwise there was little or no relationship between N-desalkylflurazepam levels and sleep efficiency or next-day behavior. Issues of tolerance, individual variability in baseline and response, and their contribution to the findings are discussed.

Methods are described for a five-center study of flurazepam and midazolam, in which 107 patients with histories of benzodiazepine use for chronic insomnia were enrolled. Data were available for 99 of these patients. Staff and patient manuals and a behavior-based computer system were specially designed to measure and delineate clearly the study procedures and parameters. Patients were carefully followed and supported during a 20-day washout period and underwent extensive training on psychomotor performance tasks. They received placebo for 2 nights and were then randomly assigned to one of four study treatments--flurazepam 15 or 30 mg, midazolam 15 mg, or placebo--for 14 consecutive nights. All-night sleep electroencephalographic recordings were obtained on study nights--1 and 0 (placebo) and 1, 2, 7, 13, and 14 (treatment nights). Results of four computer-generated psychomotor performance tasks and three cognitive tasks, plus subjective evaluations of sleep, performance, and mood, were recorded in the morning after each night spent in the sleep laboratory. Blood and urine samples were analyzed for drug concentrations in plasma and for compliance with the protocol. A pilot study, using a high (nonclinical) dose of flurazepam (45 mg), preceded the multi-center study and was designed to evaluate tests in healthy volunteers and to familiarize staff with equipment and tests.

The 99 chronic insomniacs examined in the present multicenter study were given three cognitive tasks (reading comprehension, addition, and digit symbol substitution test [DSST]) as well as the Hopkins Symptom Checklist (HSCL) and the Profile of Mood States (POMS) in order to evaluate the effects of flurazepam (Dalmane) 15 and 30 mg, midazolam 15 mg, and placebo on cognitive performance and mood. Subjective evaluation of performance was also obtained. A significant person in the patient's life was also asked to evaluate the patient's mood before and during the 14-day treatment interval. After a 20-day washout, next-day performance and mood were evaluated after placebo nights -1 and 0 (baseline) and after treatment nights 1, 2 (early interval), 7 (middle interval), and 13 and 14 (late interval). Analysis of variance (ANOVA) on changes from baseline indicated no significant between-groups treatment effects for reading comprehension or any of the mood variables at any interval. Patients on flurazepam 30 mg performed less well compared with other groups even though, after completion of the tasks, this group believed that they performed as well as those on the other regimens. Performances by flurazepam 15 mg, midazolam, and placebo groups were similar. Significant others tended to rate high-dose flurazepam patients more negatively. High-dose flurazepam patients had a significant change on the DSST and addition tasks due to treatment after the first night, and change in performance remained significantly impaired for the DSST task relative to that of the other groups thereafter.

One hundred seven chronic insomniacs (41 men, 66 women; mean age, 37.9 years) with a history of use of benzodiazepines were recruited for a multicenter study testing the relative efficacy of flurazepam 15 mg or 30 mg, midazolam 15 mg, or placebo during a 14-day treatment period. Average duration of the complaint of insomnia was 13.5 years. Most (74%) of the patients met criteria for a diagnosis of persistent psychophysiological sleep disorder for both initiating and maintaining sleep.

A review of the published literature reveals many unanswered questions regarding the effects of sedative-hypnotics on sleep, performance, and mood. The relationship between plasma half-life and hypnotic efficacy is also not clear. A randomized, double-blind, parallel-groups, multicenter study was designed to examine sleep, performance, and mood in patients with insomnia. A large, heterogeneous sample of patients with a history of benzodiazepine use for chronic insomnia was chosen to reflect the adult population for which sedative-hypnotics are often prescribed and to ensure statistical reliability. Although the major focus of the current study was on the effects of two benzodiazepine hypnotics on performance, this study also provided information on the following important issues: (1) effect of dose level; (2) short-versus long-term administration; and (3) significance of plasma half-life as it relates to hypnotic efficacy.

This article contains the sleep results of the efficacy study of flurazepam 30 mg and 15 mg, midazolam 15 mg, and placebo in the 99 chronic insomniacs studied as part of this multicenter study. After a 20-day drug washout, all-night sleep was recorded on 2 baseline nights, on the first 2 treatment nights, on treatment night 7, and on the last 2 nights of the study (nights 13 and 14). To reduce the number of comparisons, electroencephalographic (EEG) sleep latency, EEG wake time, EEG sleep efficiency, post-sleep questionnaire (PSQ) sleep latency, and PSQ total sleep were preselected as the major sleep variables. Between-groups comparisons indicated that, when compared with the placebo control, all drugs improved sleep, but differences were statistically significant only for the first 2 nights, i.e., the early interval. Midazolam was more effective than either dose level of flurazepam on treatment night 1. Within-group analyses indicated that all drug groups showed significantly improved sleep from baseline throughout drug administration, but the placebo group did not significantly improve from baseline by either objective or subjective measures at any of the three time intervals. The sleep of patients taking flurazepam 30 mg did not differ significantly from the sleep of those receiving the 15 mg dose for any of the five major sleep variables at any interval. Objective EEG and subjective PSQ sleep variables showed significant positive correlations.

A multicenter, double-blind placebo-controlled clinical trial was designed to compare the safety and efficacy of estazolam compared with flurazepam as hypnotics. Outpatients complaining of insomnia were randomized to receive either estazolam 2 mg, flurazepam 30 mg or placebo for 7 consecutive nights. The analysis of efficacy was based on the patients' daily assessments of sleep and the investigators' global evaluations. Adverse events which were considered by the investigator to be attributable to, or of unknown relationship to the test medication were analyzed. The patient subjective questionnaire indicated that estazolam and flurazepam significantly improved all parameters (P less than .05) as compared to placebo. A marked or moderate improvement in sleep was reported by 81% (58/72), 78% (63/81) and 36% (27/76) of estazolam, flurazepam, and placebo recipients, respectively. There were no significant differences in hypnotic effect between estazolam and flurazepam. All efficacy parameters of the investigators' global evaluation improved significantly more (P less than .05) for patients receiving estazolam or flurazepam (except quality of sleep) than for those receiving placebo. The percentage of patients reporting any adverse experience was greatest for flurazepam (72%), followed by estazolam (59%), and placebo (43%). Somnolence and hypokinesia were the most commonly reported adverse events. An analysis of the global evaluation of side effects showed that flurazepam had a significantly worse side effect profile than estazolam (P less than .05) or placebo (P = .001). Estazolam and flurazepam effectively, and comparably, relieved insomnia when administered for 7 nights in adult patients complaining of insomnia. Estazolam demonstrated a more favorable side effect profile than flurazepam.

A double-blind randomized parallel group design was used to compare the tolerance and efficacy of zopiclone 7.5 mg, flurazepam 30 mg and placebo taken each night for 3 weeks in a group of 24 out-patients complaining of sleep disturbance. Analogue rating scales were used to assess the efficacy of the treatments while tolerance and residual effects were measured weekly using a battery of performance tests (Critical Flicker Fusion Threshold, Choice Reaction Time, Letter Cancellation and Digit Span). Physical and clinical examinations, including ECG and EEG, were conducted before and after the experimental period and spontaneously reported side-effects were recorded. Analysis of variance on 24 completed cases (8 patients in each treatment group) showed both active treatments to be significantly better than placebo in shortening sleep onset latency. Flurazepam increased the duration of sleep and produced a "hangover" of impaired psychomotor function. Zopiclone had no observable effect on early morning performance and was free from residual sedative activity. The lack of residual effects with zopiclone 7.5 mg, at a dose shown to be clinically effective, suggests its use in ambulant or out-patient populations where daytime sedation could interfere with every day activities.

In addition to differing in ethanol sensitivity, long-sleep (LS) and short-sleep (SS) mice also differ in response to GABAergic agents. In the present study the sensitivity of LS and SS mice to the anesthetic, hypothermic and anticonvulsant effects of benzodiazepine, flurazepam, was determined. Flurazepam (75-300 mg/kg) induced a dose-dependent loss of righting response in both lines. The LS line displayed a two-fold greater sensitivity to the anesthetic effects of flurazepam. A dose-dependent decrease in body temperature was also observed following administration of flurazepam (25-150 mg/kg), but the two lines did not differ on this measure. Determination of the anticonvulsant effects of flurazepam (1-6 mg/kg) against seizures induced by 3-mercaptopropionic acid revealed that the SS line was more sensitive to the anticonvulsant effects of this benzodiazepine. These studies demonstrate that LS and SS mice differ in response to flurazepam, but the nature of the difference depends on the type of response measured and the dose of flurazepam employed.

There has been a paucity of research in the use of high-dose benzodiazepines in the treatment of severe neurotic anxiety. The author presents five cases, three with excellent and two with poor outcomes. The English and Fench language literature is reviewed and reveals evidence that high-dose benzodiazepines may be useful in the treatment of certain neurotic patients. However, the lack of controlled studies is noted. The author poses several questions important to the future of research on benzodiazepines.

A twelve-week study involving fifty-three patients is described as taking place in a practice with a higher than average geriatric population. The purpose of the study was to substitute flurazepam for habitually used barbiturates or methaqualone/diphenhydramine. Of the original fifty-three patients admitted to the study, fifty-one completed; the two drop-outs resulting from concomitant physical illness. Eighty-four per cent of patients were successfully changed to flurazepam. Of those who did not accept flurazepam, eight per cent accepted nitrazepam, while six per cent of patients were motivated to stop all hypnotics. During the three month period of the study none of the well-known disadvantages of the barbiturates and methaqualone/diphenhydramine were seen with flurazepam. The author found flurazepam to be a very efficient hypnotic of relatively low toxicity which could be easily substituted fro barbiturates and methaqualone/diphenhydramine in the treatment of long-term insomnia.

The hypnotic effects of l-tryptophan (1 g), secobarbital (100 mg), and flurazepam (30 mg), relative to placebo, were evaluated in a sample of 54 outpatient chronic insomniacs with a major complaint of sleep maintenance insomnia. Three mutually exclusive complaints about sleep maintenance were identified. Analysis of the data from the tryptophan condition indicated that the single factor type of sleep maintenance complaint accounted for 100% of the variance in a measure reflecting a single overall assessment of tryptophan's hypnotic effect, and 52% of variance in a second, repeated measure assessing subjects' day-to-day experience with the treatment. It is concluded that the distinctions in sleep maintenance insomnia identified are likely to be clinically meaningful. The distinct profiles of the tryptophan responders and nonresponders are described, and the utility of the distinctions in understanding the differential effects of flurazepam and secobarbital discussed. The implications of the finding for a number of sleep disorder-related issues were addressed.

This article describes a controlled clinical trial comparing nomifensine and amitriptyline in endogenously depressed inpatients. It is also the first trial of the ICPP-BLIPS, a computer based clinical trial data documentation system. Using strict methodological criteria, careful quality control and comprehensive and systematic data display and data analysis, we have been able to show clearcut efficacy differences between nomifensine and amitriptyline (favouring the later) and clearcut differences in the profile of side effects between these drugs. Future studies utilizing this methodology are recommended were definitive and documented results of clinical trials are desired.

Zopiclone is a new nonbenzodiazepine hypnotic, the recommended dose of which is 7.5 mg. It was compared to flurazepam 30 mg in a sleep laboratory study. 12 women aged 40-60 years, with subjective sleep disorders for at least 2 months, were treated for 13 nights with each drug in a crossover double-blind design. Each active drug period was preceded by 5 days of placebo washout and followed by 35 days of withdrawal (no treatment). A baseline period of 4 nights (without treatment) was obtained before the study itself. The subjects slept in the sleep laboratory during the baseline period, during the last 3 nights on placebo, during the last 3 nights on active drug, and from the 11th to the 13th night after active drug discontinuation. Polygraphic recordings were obtained during each of these nights. The criteria of Kales and Rechtschaffen were used to score the tracings. Both drugs were shown to be effective when compared to placebo. Comparisons between the two periods with active treatment did not show significant differences for sleep onset latency, total sleep time, sleep efficiency index, stage 0, percent REM, number of REM periods, and REM latency. There was a trend towards an increase with zopiclone of the number of awakenings, percent of stage 3, percent of deep sleep, and an increase with flurazepam of the percent of light sleep. A significant difference was only found for percent of stage 2 (increased with flurazepam).

Valproate exhibits potent antiepileptic and antimyoclonic activity in a number of clinical and experimental syndromes. The mechanism of action of valproate remains unknown, but several neurotransmitter systems are affected directly or indirectly by valproate administration. The levels of the serotonin precursor and the principal serotonin metabolite, tryptophan and 5-hydroxyindoleacetic acid, respectively, are elevated in rodent brain following the administration of anticonvulsant doses of valproate. However, the anticonvulsant action of valproate is preserved in mice pretreated with p-chlorophenylalanine, which depletes the brain levels of serotonin and serotonin metabolites. Valproate administration elevates the level of the inhibitory transmitter glycine in the urine and plasma of patients and experimental animals, and the hepatic glycine cleavage enzyme is inhibited by valproate. The cerebral glycine levels in rodents are not affected by valproate administration, and the inhibitory action of glycine on reticular neuron firing is not affected by iontophoretically applied valproate. Valproate exerts multiple effects on the inhibitory GABA transmitter system. Elevation in brain GABA level occurs in parallel with the anticonvulsant activity observed following valproate administration, and high levels of valproate inhibit the GABA-metabolizing enzymes GABA-T and SSADH and cause a reduction in the rate of GABA turnover. Valproate has no effect on GABA uptake, release, or binding to the GABA receptor complex. Iontophoretically applied valproate augments the inhibitory action of GABA on neuronal firing in a number of brain regions including the reticular formation. Excitatory amino acid antagonists have recently been shown to possess anticonvulsant and antimyoclonic activity in a number of animal models. The ability of these compounds to decrease the brain level of the excitatory transmitter aspartate is shared by valproate. The valproate-induced decrease in aspartate level is dose dependent and coincides with the period of anticonvulsant protection. There is also a strong correlation between the anticonvulsant potency of a number of valproate analogs and their ability to reduce cerebral aspartate levels.