Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

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.

Interventions to reduce bruxism in children and adolescents: a systematic scoping review and critical reflection.

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: a case report.

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.

Testing the silence of mutations: Transcriptomic and behavioral studies of GABA(A) receptor α1 and α2 subunit knock-in mice.

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.

Effects of discontinuing benzodiazepine-derivative hypnotics on postural sway and cognitive functions in the elderly.

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.

Genetically inbred Balb/C mice are more sensitive to an effect of flurazepam and more resistant to an effect of stress than a genetically outbred mouse strain.

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.

Flexible modeling of the cumulative effects of time-dependent exposures on the hazard.

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.

An epigenetic intervention interacts with genetic strain differences to modulate the stress-induced reduction of flurazepam's antiseizure efficacy in the mouse.

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.

Toxic epidermal necrolysis caused by flurazepam?

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.

[Diagnostics and treatment of insomnia with concomitant arterial hypertension. Use of somnol as an adjuvant remedy]. / Diagnostika i lechenie insomnii pri arterial'noi gipertenzii. Primenenie Somnola kak ad'iuvantnogo sredstva.

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.

Behavioral and hypnotic treatments for insomnia subtypes.

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.

Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia.

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.

Effects of flurazepam and zolpidem on the perception of sleep in normal volunteers.

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.

Effects of flurazepam and zolpidem on the perception of sleep in 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.

Management of insomnia in office-based practice. National prevalence and therapeutic patterns.

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.

Diagnosis and treatment of outpatient insomnia by psychiatric and nonpsychiatric physicians.

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.

Pharmacology of benzodiazepine hypnotics.

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.