Factors associated with the long-term use of benzodiazepine receptor agonists as hypnotics among patients with major depressive disorder and comorbid insomnia.

BACKGROUND: Patients with major depressive disorder (MDD) and comorbid insomnia are often co-prescribed benzodiazepines (BZDs) or Z-drugs as hypnotics with antidepressants to manage persistent insomnia. However, factors associated with their long-term use remain unclear among MDD patients. METHODS: We retrospectively analyzed data from 351 MDD patients who started antidepressants with co-prescribed hypnotics (BZDs/Z-drugs) and investigated the prevalence of and factors associated with their long-term use at 12 months. We conducted logistic regression analyses of their long-term use, and compared insomnia severities between the continued and discontinued groups of hypnotics in 32 patients whose insomnia severities had been longitudinally assessed. RESULTS: 66.1% of patients had continued hypnotics for 12 months. Multiple logistic regression analysis revealed that the diazepam-equivalent dose of hypnotics at the start of the combined treatment (>5 mg), the presence of chronic insomnia prior to MDD, and hospitalization correlated with their long-term use (all p < 0.01). We also found the relationship between the insufficient amelioration of insomnia severities and their long-term use. However, confidence in these results is tempered by various factors, including the dependence on hypnotics, the patient's attitude about hypnotic treatment, and the exclusion of subjects treated with other drugs such as sedative antidepressants or antipsychotics. CONCLUSIONS: These clinical indicators may facilitate the selection of treatment strategies for MDD with comorbid insomnia. To avoid the long-term use of hypnotics, their dose at the start of the combined treatment needs to be adequate (≤5 mg) and alternative treatments to BZDs/Z-drugs are required for refractory insomnia.

Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.

Trends in the multiple prescriptions of hypnotic drugs in a university outpatient in Japan.

AIMS: In Japan, the daily dosage of hypnotic drugs for insomnia treatment is increasing year by year, and over-dependence on treatment with hypnotic drugs is a major problem. This study aimed to examine the factors related to the elimination of prescriptions of three or more hypnotic drugs within 1 year in our clinic. METHODS: We conducted two surveys. Survey ① assessed the frequency of prescriptions of three or more hypnotic drugs by retrospectively reviewing the medical records of all patients who visited general and psychiatric outpatient clinics from January 2013 to March 2019. Survey ② assessed changes in prescriptions of hypnotic and psychotropic drugs within the subsequent year by retrospectively reviewing the medical records of all patients prescribed three or more hypnotic drugs who visited neuropsychiatric outpatient clinics multiple times between April 2013 and March 2019. RESULTS: The frequency of prescribing three or more hypnotic drugs was six to nine times higher in psychiatry than in other departments. Flunitrazepam and brotizolam were the most common drugs prescribed and had the second lowest discontinuation rate after zolpidem. Conversely, eszopiclone, zopiclone, and suvorexant had the highest discontinuation rates. The success factors for drug reduction were age (odds ratio [OR]: 0.97, p < 0.0037), trazodone addition (OR: 12.86, p < 0.0194) and number of years of psychiatric experience. CONCLUSIONS: The characteristics and success factors in relation to drug reduction in patients with multiple prescriptions of hypnotic drugs identified in this study may contribute to solving the problem of multiple prescriptions of hypnotic drugs.

Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire.

AIMS: Benzodiazepine receptor agonists (BZ-RAs) are frequently prescribed to treat insomnia; however, their long-term use is not recommended. To introduce an appropriate pharmaco-therapy, the current state and background factors of BZ-RAs' dependence must be elucidated. In this study, we developed a Japanese version of the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ-J) and conducted a study of BZ-RAs' use disorder. METHODS: The Bendep-SRQ-J was created with permission from the original developer. Subjects were inpatients and outpatients receiving BZ-RAs between 2012 and 2013. Clinical data collected were Bendep-SRQ-J scores, sleep disorders for which BZ-RAs were prescribed, physical comorbidities, psychotropic drugs, and lifestyle factors. Logistic analysis was performed to extract factors associated with severe symptoms. RESULTS: Of the 707 patients prescribed BZ-RAs, 324 had voluntarily tapered or discontinued their drugs. Logistic analysis showed that the total number of drugs administered in the last 6 months correlated with both worsening of symptoms or conditions. This was more notable among younger patients, and the proportion of patients with severe symptoms or conditions increased with the increasing number of drugs. CONCLUSION: Using the Bendep-SRQ-J, we elucidated the current state of BZ-RA dependence. Nearly half of the patients were non-compliant. The proportion of patients with severe symptoms or disease conditions increased with the increase in the number of drugs administered. These findings highlight the need for clinicians to be aware of the likelihood of benzodiazepine dependence, especially in young patients and patients prescribed multiple hypnotics.

Polysomnographic Sleep Disturbances Due to High-Dose Zolpidem Use: A Case Report.

ABSTRACT: Zolpidem is widely prescribed for the treatment of insomnia and is used to both induce and maintain sleep. Previously, zolpidem was thought to have low abuse potential; however, several reports have documented dose escalation and abuse in the past two decades. Here, we report the case of a patient with high-dose zolpidem dependence who underwent polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). The patient, a 29-year-old man, was administered zolpidem at doses of 300 to 1,200 mg/day, but he abused zolpidem to feel energetic. Consequently, he had a car accident while on a high dose, which the PSG revealed caused activation instead of sedation. The MSLT showed excessive daytime sleepiness despite a lack of subjective sleepiness under this condition. Our findings suggest that disrupted sleep and daytime sleepiness caused by supratherapeutic zolpidem doses could place individuals at high risk for accidents, including those who are unaware of sleepiness.

Differences in rapid eye movement (REM) sleep abnormalities between posttraumatic stress disorder (PTSD) and major depressive disorder patients: REM interruption correlated with nightmare complaints in PTSD.

OBJECTIVE: The presence of repeated nightmares in posttraumatic stress disorder (PTSD) has been hypothesized as a dysfunction of rapid eye movement (REM) sleep, but there has been remarkably little agreement about the pathophysiology. This presents a deterrent to more effective treatments. REM sleep abnormalities including elevated REM density also have been replicated in major depressive disorder (MDD). The purpose of this study was to clarify the difference of REM sleep abnormalities between the two disorders for understanding the pathophysiology of sleep disturbances in PTSD. METHODS: Polysomnographic measures were compared among 14 PTSD patients (aged 23.7 ± 5.5 years) and 14 MDD patients (aged 27.9 ± 10.1 years) under drug-naive or drug-free conditions. We defined REM interruption by summing the intrusive wake times during the REM period and adding the subsequent wake times to the last epoch of REM period. The significant polysomnographic measures were correlated with PTSD symptoms within the PTSD group. RESULTS: REM interruption was significantly increased in the PTSD group compared with the MDD group (12.2 vs 2.1 min, p = 0.001). REM density was also significantly increased in the PTSD group compared with the MDD group (30.5 vs 23.1%, p = 0.019). Within the PTSD group, we found significant correlations between the severity of trauma-related nightmare complaints and the percentage of REM interruption (R = 0.62, p = 0.017), but not REM density. CONCLUSIONS: REM sleep abnormalities are different between PTSD and MDD. Increased REM interruption may be a biological marker correlated with nightmare complaints in PTSD patients. Treatments including pharmacotherapy that reduces REM interruption might ameliorate nightmares in PTSD.

Effect of CPAP treatment on residual depressive symptoms in patients with major depression and coexisting sleep apnea: Contribution of daytime sleepiness to residual depressive symptoms.

BACKGROUND: Although extensive studies have indicated a relationship between obstructive sleep apnea (OSA) and depressive symptoms, the effect of continuous positive airway pressure (CPAP) treatment on residual depressive symptoms in patients with both major depressive disorder (MDD) and coexisting OSA has not been examined. METHODS: Seventeen patients with continued MDD despite pharmacotherapy such as antidepressants and/or benzodiazepines, who also had comorbid OSA, were required to complete the Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HRSD), and Epworth sleepiness scale (ESS) at the commencement of the study and then again after 2 months of CPAP treatment. RESULTS: BDI and HRSD scores decreased from 19.7 to 10.8 and 16.7 to 8.0 after 2 months of CPAP treatment (both p<0.01). We also found significant correlations among the improvement rates in BDI, HRSD and ESS scores (R=0.86 and 0.75, both p<0.01). The mixed effect model demonstrated a significant ESS effect on BDI and HRSD. CONCLUSIONS: The results suggest that MDD patients with residual depressive symptoms despite pharmacotherapy who also have symptoms of suspected OSA, such as loud snoring, obesity, and daytime sleepiness, should be evaluated for sleep apnea by polysomnography and treated with an appropriate treatment such as CPAP. CPAP treatment may result in a significant improvement of residual depressive symptoms due to the improvement of daytime sleepiness in these patients.

Sleep findings in young adult patients with posttraumatic stress disorder.

BACKGROUND: Laboratory sleep studies in posttraumatic stress disorder (PTSD) have not provided consistent evidence of sleep disturbance, despite apparent sleep complaints. Most of these studies have investigated middle-aged chronic PTSD subjects with a high prevalence of comorbidities such as substance dependence and/or personality disorder. METHODS: Ten young adult PTSD patients (aged 23.4 +/- 6.1 years) without comorbidities of substance dependence and/or personality disorder underwent 2-night polysomnographic recordings. These sleep measures were compared with those of normal control subjects and were correlated with PTSD symptoms. RESULTS: Posttraumatic stress disorder patients demonstrated significantly poorer sleep, reduced sleep efficiency caused by increased wake time after sleep onset, and increased awakening from rapid eye movement (REM) sleep (REM interruption). We found significant positive correlations between the severity of trauma-related nightmare complaints and the percentage of REM interruption, as well as wake time after sleep onset. CONCLUSIONS: The results indicate that trauma-related nightmares are an important factor resulting in increased REM interruptions and wake time after sleep onset in PTSD.

Effect of zolpidem on sleep architecture and its next-morning residual effect in insomniac patients: a randomized crossover comparative study with brotizolam.

This study was conducted to determine the effect of zolpidem (ZOL) 10 mg orally on the sleep architecture and the next-morning residual effect in patients with non-organic insomnia (ICD-10) as compared to the effect of brotizolam (BTM) 0.25 mg orally, a widely used short-acting benzodiazepine (BZD) hypnotic in Japan, in a randomized, crossover comparative study. Fourteen patients with non-organic insomnia (3 males and 11 females; mean age of 54.9+/-S.D. 8.9 years). First three nights with placebo, middle three nights with either ZOL 10 mg or BTM 0.25 mg, and last three nights again with placebo in each session (a total of two sessions). Primary endpoints were polysomnography findings of sleep stages, sleep parameters, and sleep latency (SL) in the morning to examine calculable sleepiness as a residual effect. Secondary endpoint was sleep quality assessed by self-assessment questionnaire. At 150 min after Tmax, both ZOL and BTM significantly increased stage 2 (S2), and ZOL showed significantly longer slow wave sleep (SWS; stage 3+4) as compared to BTM. Stage wake was significantly increased by ZOL at the first withdrawal night and by BTM at the second withdrawal night. ZOL did not affect SL after rising, whereas BTM showed significantly shorter SL. Both drugs reduced the number of nocturnal awakenings and improved subjective sleep quality. The common adverse drug reaction (ADR) was sleepiness (3 patients) in each treatment. All events were mild. No serious adverse events occurred. ZOL is as effective as BTM in improving subjective sleep quality in patients with psychophysiological insomnia (PPI). ZOL has advantages over BTM in having a unique profile of increasing SWS with less next-morning residual effect.