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.

[Comparative evaluation of the hypnotic drugs under conditions of brain injury].

The effect of hypnotic drugs on the brain stability with respect to complete ischemia posttraumatic convulsive reactions and hypoxia has been studied in animals with model brain injury. It is established that zopiclone exhibits pronounced hypnotic effect during the first and second week after brain injury, while nitrazepam, zolpidem, and melaxen are effective in the first week. The neuroprotective effects of zopiclone and zolpidem are more pronounced than those of melaxen and nitrazepam.

Effectiveness and Safety of Nitrazepam in Children with Resistant West Syndrome.

OBJECTIVES: To study the effectiveness, tolerability, and safety of oral nitrazepam in children with resistant West syndrome (WS). METHODS: This prospective observational study was conducted at a tertiary care hospital in North India from January 2019 to October 2020. Children with WS resistant to standard therapy were enrolled within 7 d of initiation of nitrazepam and prospectively followed-up for cessation of spasms and adverse events. RESULTS: Forty-one children with resistant WS initiated on nitrazepam therapy were evaluated. The median age at onset of spasms was 6 mo (Q1, Q3: 4, 8). There was a preponderance of male gender (71%) and structural causes (78%). More than half of the enrolled children had failed four or more antiseizure medications (ASM) for epileptic spasms. The study participants had a long lead-time-to-treatment (LTTT) for the initial standard therapy (median: 2 mo; Q1, Q3: 1, 5) and nitrazepam (median: 11 mo; Q1, Q3: 8, 16). Nitrazepam was instituted as monotherapy in 7 (17%) children and as an adjunct in the rest. Twenty-one (51%) children achieved persistent cessation of epileptic spasms. However, the electroclinical response was observed in 17 (42%) children. Drowsiness, sialorrhea, and decreased appetite were the most commonly observed adverse events. Most adverse events were mild to moderate in severity and did not require dose reduction or change of medication. There was no significant difference between the responders and nonresponders in terms of LTTT, age at onset, or etiology. CONCLUSIONS: Nitrazepam is a safe and feasible treatment alternative in children with resistant WS resulting in persistent cessation of spasms and electroclinical response in nearly half of patients.

Oral S-ketamine effective after deep brain stimulation in severe treatment-resistant depression and extensive comorbidities.

This case report describes successful maintenance treatment with oral S-ketamine in a patient with severe depression, who previously was resistant to electroconvulsive therapy and deep brain stimulation, and who also had comorbid psychotic and obsessive compulsive symptoms.

The effect of placebo administration on the first-night effect in healthy young volunteers.

The first-night effect is a well-known phenomenon that is considered to result from a subject's lack of adaptation to the unfamiliar environment of a sleep laboratory and to the technical equipment used for polysomnography. The effect has been explored as a laboratory model for transient insomnia. The main characteristics of this effect are short total sleep time (TST) and rapid eye movement (REM) sleep, a lower sleep efficiency index, and longer REM sleep latency. Previous studies have reported that personality traits (such as trait anxiety) are a potential cause of the first-night effect and that the placebo effect is closely related to the anxiety levels of the subjects. To the best of our knowledge, there are no reports regarding the effects of a placebo on first-night sleep. This omission can be explained by the fact that the polysomnographic recordings obtained during the first night of a study are generally excluded from the analysis in order to avoid the inclusion of the first-night effect. In the present study, 8 male university students were subjected to polysomnographic examinations during drug-free, placebo-administration, and benzodiazepine-administration conditions in order to clarify the placebo effect on sleep during consecutive nights, particularly on the first night. The recordings for each condition were conducted for 4 consecutive nights. A placebo or 5 mg nitrazepam was administered at 2230 h using a double-blind crossover design, while no drug was administered during the drug-free condition. There was a 10-day interval between the examination of each condition. Polysomnographic recording was started at 2300 h and continued until the natural awakening of the subjects on the next morning. Subsequently, the subjects were requested to fill in a rating scale that is used to evaluate the subjective perception of sleep. An increase in stage-2 sleep associated with the first-night effect was observed on the first night during the drug-free and placebo-administration conditions. However, REM sleep reduction associated with the first-night effect was detected on the first night during the drug-free condition; this decrease in REM sleep was counteracted by the placebo during the placebo-administration condition. The nitrazepam, but not the placebo, decreased both slow-wave sleep (SWS) and REM sleep. The values for the tendency to fall asleep, feeling refreshed upon awakening in the morning, and the tension upon awakening in the morning were improved to a greater extent by the placebo and nitrazepam administrations than when no drug was administered. These results demonstrate the possibility that placebo administration may have a hypnotic/anxiolytic effect and may improve transient insomnia without causing SWS and REM sleep reductions.

Treatment of infantile spasms with sodium valproate followed by benzodiazepines.

OBJECTIVE: To review the result of the infantile spasms' treatment with sodium valproate followed by nitrazepam or clonazepam. STUDY DESIGN: Descriptive retrospective study. SETTING: Srinagarind Hospital, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. MATERIAL AND METHOD: Twenty-four infantile spasms admitted between January 1994 and December 2003 were analyzed. The inclusion criteria were the patients with infantile spasms clinically diagnosed by the pediatric neurologist, having hypsarrhythmic pattern EEG, and receiving sodium valproate with or without nitrazepam or clonazepam. The patients who had an uncertain diagnosis, incomplete medical record, or that were incompletely followed up were excluded. Data were collected on sex, age at onset of seizure, type of infantile spasms, associated type of seizure, predisposing etiological factor, neuroimaging study, and the result of treatment including cessation of spasms, subsequent development of other seizure types, quantitative reduction of spasms, relapse rates of spasms, psychomotor development, and adverse effects of AEDs. RESULTS: The mean age at onset was 177 days. The male-to-female ratio was 1:1.2. There were 13 cryptogenic (54.2%) and 11 symptomatic (45.8%) infantile spasms. The most common predisposing etiological factors in symptomatic cases were hypoxic ischemic encephalopathy (45.5%) and microcephaly (36.4%), respectively. Ten patients received sodium valproate (41.7%), another 10 received sodium valproate with clonazepam (41.7%), and four received sodium valproate with nitrazepam (16.7%). Both, the complete cessation rate and the 50% reduction of spasms rate were 45.8%. The duration to complete cessation was 70 days. The relapse rate was 18.2%. The rate of delayed psychomotor development was 83.3%. The mean duration of follow-up was 49.6 months. CONCLUSION: The authors propose to use sodium valproate concomitantly with benzodiazepines, especially clonazepam, in situations such as unavailability, intolerability, or adverse effects of ACTH or vigabatrin, or in a patient who does not respond to ACTH or vigabatrin.

Health risk appraisal in older people 7: long-acting benzodiazepine use in community-dwelling older adults in London: is it related to physical or psychological factors?

Aim To investigate whether the use of long-acting benzodiazepines, in individuals aged 65 and over is mediated by physical or psychological factors. BACKGROUND: Long-acting benzodiazepine consumption among older people has implications for mortality, morbidity and cost-effective prescribing. Two models explain benzodiazepine use in this age group, one linked to physical illness and disability and one to psychological factors. METHODS: Secondary analysis of baseline data from a study of 1059 community-dwelling non-disabled people aged 65 years and over recruited from three general practices in London. For this analysis, use of long-acting benzodiazepines was defined as any self-reported use of diazepam or nitrazepam in the last four weeks. Associations between demographic factors, health service use, and physical and psychological characteristics and benzodiazepine use were investigated. Findings The prevalence of benzodiazepine use in this sample was 3.3% (35/1059). In univariate analyses, benzodiazepine use was associated with female gender, low income, high consultation rates, physical factors (medication for arthritis or joint pain, polypharmacy, difficulties in instrumental activities of daily living, recent pain) and psychological factors (poor self-perceived health, social isolation, and symptoms of anxiety or agitation). In a multivariate logistic regression analysis only two factors retained statistically significant independent associations with benzodiazepine use: receiving only the state pension (OR=4.0, 95% CI: 1.70, 9.80) and pain in the past four weeks (OR=3.79, 95% CI: 1.36, 10.54).

Caracterización de la prescripción de ansiolíticos en adultos mayores institucionalizados en un hogar de ancianos / Characterization of the prescription of anxiolytics in institutionalized older adults in the nursing home

El objetivo de este estudio fue caracterizar la prescripción de los medicamentos ansiolíticos utilizados en población de adultos mayores institucionalizados en el hogar de ancianos de Pinar del Río durante el año 2017.Se realizó un estudio descriptivo transversal, con recogida de datos retrospectiva, sobre prescripción de medicamentos ansiolíticos en la población de adultos mayores institucionalizados en el hogar de ancianos, se analizó la forma de utilización de los medicamentos, su indicación y prescripción con elementos de esquema terapéutico y factores que condicionan los hábitos de prescripción. Se trabajó con el universo (U= 98) de estudio el cual estuvo conformado por el total de pacientes institucionalizados, que estaban consumiendo ansiolíticos. Se revisaron las historias clínicas individuales y se confeccionó un modelo de recolección de datos.El medicamento más consumido por los adultos mayores fue el nitrazepam (41,8 %), siendo este a su vez el más consumido por el sexo masculino, no así para el femenino que resultó ser el clorodiazepóxido (64,6 %), el grupo de edad que más predominó fue el de 60-69 años, asimismo los viudos y el nivel educacional primario, el 79,5 % de los ancianos consume otros medicamentos que poseen interacción farmacocinética. El profesional que más indicó fue el médico de familia, la prescripción e intervalos entre dosis fue adecuada, la prescripción se consideró no racional.La prescripción de ansiolíticos en la población objeto de estudio, disminuye a medida que aumenta la edad, los más consumidores son los del sexo masculino y los institucionalizados por abandono familiar, esto apunta a la necesidad de continuar trabajando desde el nivel primario de atención dado que es de donde proceden estos ancianos.

The objective of this study was to characterize the prescription of anxiolytic medications used in the institutionalized elderly population at the Pinar del Río Nursing Home during 2017.A cross-sectional descriptive study was carried out, with retrospective data collection, on the prescription of anxiolytic medications in the population of institutionalized older adults in the Nursing Home, the form of use of the medications, their indication and prescription with elements of the therapeutic scheme was analyzed and factors that condition prescription habits. We worked with the universe (U = 98) of the study, which was made up of the total number of institutionalized patients who were consuming anxiolytics. Individual medical records were reviewed and a data collection model was created.The drug most consumed by older adults was nitrazepam (41.8%), this in turn being the most consumed by males, not so for females, which turned out to be chlorodiazepoxide (64.6%), the group The most prevalent age group was 60-69 years, likewise widowers and primary educational level, 79.5% of the elderly consume other drugs that have pharmacokinetic interaction. The professional who indicated the most was the family doctor, the prescription and intervals between doses were adequate, the prescription was considered non-rational.The prescription of anxiolytics in the population under study decreases as age increases, the most consumers are those of the male sex and those institutionalized due to family abandonment, this points to the need to continue working from the primary level of care since that is where these elders come from.

The effect of nitrazepam on depression and curiosity in behavioral tests in mice: The role of potassium channels.

Evidence show that gamma-aminobutyric acid (GABA) receptors are involved in depression, so the aim of this study was to investigate the effect of nitrazepam as agonist of GABAA receptors on depression and curiosity in male mice and the role of potassium channel in antidepressant-like response. For this purpose, we studied the antidepressant-like properties of fluoxetine, nitrazepam, glibenclamide, and cromakalim by both forced swimming test (FST) and tail suspension test (TST). Animals were injected by various doses of nitrazepam (0.05, 0.1, and 0.5mg/kg). Nitrazepam at dose of 0.5mg/kg significantly decreased the immobility time compared to control group in both FST and TST. Fluoxetine also showed such a response. Co-administration of nitrazepam (0.05mg/kg) with glibenclamide in TST (1mg/kg) and in FST (0.3, 1mg/kg) also showed antidepressant-like response. Beside, cromakalim (0.1mg/kg) could reverse the antidepressant-like effect of nitrazepam (0.5mg/kg) in both FST and TST, while cromakalim and glibenclamide alone could not change the immobility time compared to control group (P>0.05). The hole-board test revealed that nitrazepam at doses of 0.5 and 0.1mg/kg could increase the activity of the animal's head-dipping and boost the curiosity and exploration behavior of mice. The results of this study revealed that nitrazepam may possess antidepressant-like properties and this effect is dependent to potassium channels in both FST and TST.

Skin conductance habituation and cerebrospinal fluid 5-hydroxyindoleacetic acid in suicidal patients.

The concentration of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and psychophysiologic variables, such as habituation of the skin conductance response, were measured in 35 drug-free, suicidal inpatients. Twenty-four patients were hospitalized after a suicide attempt, and another 11 had suicidal ideation. The suicide attempters were classified into nonviolent (drug overdoses taken orally, or a single wrist cut) and violent (all other methods). As in previous studies, the suicide attempters had significantly lower CSF concentrations of 5-HIAA compared with healthy, matched controls. The distribution of habituation rate was bimodal (slow and fast habituators). All violent attempters were fast habituators, as were all four patients who in a one-year follow-up were found to have completed a suicide (all by violent methods). The lowest frequency of fast habituators was found in the group of patients with suicidal ideation. There was no correlation between CSF 5-HIAA and habituation rate. A combination of these two variables yielded a highly significant correlation with type of suicide behavior, both retrospectively and prospectively.

Absence seizures: valproate or ethosuximide?

A series of 47 children with absence seizures was analysed retrospectively. Fourteen of these children also had other types of seizures, and four had repeated episodes of absence status. The age at onset of absence seizures ranged from 1 1/2 to 13 years (mean, 7.9 years). The mean follow-up was 5.5 years. Ethosuximide (ESM) was used as the drug of first choice in 43 children, and valproate (VPA) was used first in 4 children; 15 of the patients later received VPA alone or in combination with ESM. A 100% reduction in seizure frequency was achieved in 38 children (80.8%). Of these, 23 has received ESM (21 ESM; 2 ESM + nitrazepam) and 15 had received VPA (6 VPA; 9 VPA + ESM). Of the latter group, 11 children had had an unsuccessful trial of ESM. VPA was superior in the treatment of children who had EEG polyspikes or absence status. A seizure reduction of 50% to 75% was achieved in 7 children (14.9%). Two patients (4.3%) had refractory seizures. A transient Stevens-Johnson syndrome occurred in a patient treated with ESM. Other side effects were mild and transient. Both ESM and VPA are needed in the treatment of absence seizures. In refractory cases, the combination of these drugs appears to be beneficial.

Infantile spasms. Comparative trial of nitrazepam and corticotropin.

Fifty-two patients were enrolled in a four-week randomized multicenter study comparing nitrazepam and corticotropin in the treatment of infantile spasms. The drugs' efficacy was evaluated in 48 patients, all less than 2 years of age. Both treatments resulted in a statistically significant reduction in spasm frequency from that at baseline, but the difference between treatments was not significant. The number of patients who experienced side effects was similar in the two treatment groups, but the adverse effects encountered among the patients treated with corticotropin were qualitatively more severe and required the discontinuation of treatment in six patients.

Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia.

Loprazolam is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1 mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies. Thus, with its 'intermediate' elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.

Zopiclone versus nitrazepam: a double-blind comparative study of efficacy and tolerance in elderly patients with chronic insomnia.

A randomized, double-blind, comparative trial of zopiclone versus nitrazepam was conducted in 74 geriatric chronic insomniac patients. Following a 7-day wash-out period, two parallel groups, successively received a placebo for 7 days, then either 7.5 mg zopiclone or 5 mg nitrazepam for another 7-day period. Efficacy on sleep was assessed by a sleep analogue scale and the Spiegel Sleep Questionnaire, residual effects by psychometric tests and tolerance by a standardized question, as well as by clinical and laboratory tests. Zopiclone and nitrazepam were more active than placebo on all tests of efficacy. In contrast with nitrazepam, zopiclone was devoid of effect on neurological function. In addition, the condition on awakening was better with zopiclone.

Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice.

The efficacy and tolerance of zopiclone were compared with nitrazepam and placebo in a multicenter double-blind parallel-group study in insomniac patients. Following a 7-day placebo washout period, 99 patients (age range 20 to 69 years) received oral capsules of 7.5 mg zopiclone or 5 mg nitrazepam or placebo for 2 weeks. During the fourth week all patients received placebo treatment. Sleep assessments by the patients showed that, compared with placebo, zopiclone and nitrazepam improved all sleep measures of efficacy from the first night and that effectiveness was maintained throughout treatment. The physicians global assessment of efficacy also favored zopiclone and nitrazepam over placebo treatment. Subjective morning drowsiness during treatment was significantly less for zopiclone than for either nitrazepam or placebo and represents a clear advantage for ambulatory patients. No rebound insomnia was evident during a 7 day post-treatment withdrawal period for either zopiclone or nitrazepam. Tolerance was good for all treatments.

Chronic administration of zopiclone and nitrazepam in the treatment of insomnia.

The hypnotic effects of 7.5 mg zopiclone, as well as its unwanted and residual effects, were compared with those of 5 mg nitrazepam in a double-blind, randomized, multicenter, parallel group study. After an initial, 7-day, placebo wash-out period, insomniac out-patients under the care of general practitioners received either 7.5 mg zopiclone or 5 mg nitrazepam for 6 weeks. Everyday, the patients filled in a diary (analogue scales for sleep parameters and condition during daytime); a sleep questionnaire was filled in at baseline and at the end of active treatment period; every 2 weeks, a somatic complaint check-list inventory and a mood rating scale were filled in and psychomotor tests performed; and at the end of the study, a global evaluation of efficacy and acceptability was given by the investigator. Clinical laboratory tests were performed before and after the active treatment period. From the diary, sleep onset latency, as well as sleep quality, were similarly improved by both drugs throughout the whole study. From the sleep questionnaire, all sleep parameters measured were improved at the end of the 6-week treatment period in both groups. No statistical differences in the various psychomotor tests were observed between the two treatment groups, and a significant improvement in the working ability of patients was noted with both drugs. Some significant differences were observed in the mood rating scale and the somatic complaint check list, probably related to differences in pharmacokinetics of the two drugs.

The effects of nitrazepam and flunitrazepam on oxygen desaturation during sleep in patients with stable hypoxemic nonhypercapnic COPD.

Serious respiratory depression has been described in COPD patients receiving hypnotics during acute exacerbations. There are few studies quantifying the effects of hypnotics on oxygenation during sleep in patients with stable hypoxemic COPD. In this study, the effects of single therapeutic doses of nitrazepam and flunitrazepam on SaO2, apneas during sleep and other sleep variables were measured in 14 COPD patients. All patients used theophylline. Sleep-induced decrease in mean SaO2 was 1.3 percent after placebo, 1.4 percent after nitrazepam and 1.9 percent after flunitrazepam (no significant differences). Sleep apneas were not more common or longer after nitrazepam or flunitrazepam, but sleep quality seemed to improve. It is concluded that oxygenation during sleep in these nonobese patients with stable hypoxemic nonhypercapnic COPD, all on maintenance theophylline therapy, was affected very little by single therapeutic doses of nitrazepam or flunitrazepam.

Long-term nitrazepam treatment in psychiatric out-patients with insomnia.

Psychiatric patients (N = 26) were treated chronically (from 1 week to 12 years) with nitrazepam, because of insomnia. The patients gave their subjective estimations of the effects and side effects of nitrazepam. The concentrations of nitrazepam in the plasma were measured by 63Ni-EC-gas-liquid chromatography. The pharmacokinetics of nitrazepam were compared between the psychiatric patients and healthy volunteers (N = 11). The steady-state concentrations and the half-life of nitrazepam in the psychiatric patients were comparable to those of the healthy volunteers. The subjective hypnotic effect of nitrazepam was mostly good or satisfactory and remained unchanged during long-term treatment. Only a few, mild side effects were reported. Nitrazepam does not seem to cause enzyme induction with lowered plasma levels and may therefore be of special value in the treatment of chronic insomnia.

Flunitrazepam and nitrazepam as hypnotics in psychogeriatric inpatients.

The efficacy and clinical effects of flunitrazepam (1 mg) and nitrazepam (5 mg) as somnifacients were studied in 37 psychogeriatric inpatients. Each drug was administered in a double-blind manner to randomized groups of patients for 14 nights. Compared with placebo, both benzodiazepines proved to be effective in inducing and maintaining sleep. Although both drugs were well tolerated, insomnia resulted when each was withdrawn.