Association between benzodiazepine anxiolytic polypharmacy and concomitant psychotropic medications in Japan: a retrospective cross-sectional study.

Introduction: Guidelines for various psychiatric disorders recommend short-term use of benzodiazepine anxiolytic monotherapy in few cases. Contrarily, benzodiazepine anxiolytic polypharmacy (BAP) is not recommended in any case. However, BAP is often used in real world. Therefore, this study aimed to determine the association between BAP and concomitant use of psychotropic medications. Method: This retrospective cross-sectional study used claims data from the Japan Medical Data Center. Medical information of health insurance subscribers treated with benzodiazepine anxiolytics in June 2019 was extracted. Prescription of two or more benzodiazepine anxiolytics was defined as BAP. Binary logistic regression analysis was performed to investigate the factors associated with BAP, using age group, sex, type of subscriber, and number of concomitant hypnotics, antidepressants, and antipsychotics (none, one, and two or more) as covariates. Result: The eligible participants were 104,796 adults who were prescribed benzodiazepine anxiolytics. Among them, 12.6% were prescribed two or more drugs. Logistic regression analysis revealed that BAP was significantly associated with those who received hypnotic monotherapy (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.001-1.09, p=0.04), antidepressant monotherapy and polypharmacy (aOR: 1.57, 95% CI: 1.51-1.63, p<0.001 and aOR: 1.98, 95% CI: 1.88-2.09, p<0.001, respectively), and antipsychotic monotherapy and polypharmacy (aOR: 1.12, 95% CI: 1.07-1.19, p<0.001 and aOR: 1.41, 95% CI: 1.30-1.54, p<0.001, respectively). Conversely, lower BAP was associated with those who received hypnotic polypharmacy (aOR: 0.86, 95% CI: 0.81-0.91, p<0.001). Discussion: This study showed that the greater the number of concomitant antidepressants and antipsychotics, the greater the association with BAP. Since combination therapy with antidepressants or antipsychotics is generally not recommended, patients receiving combination therapy with these medications may be resistant to pharmacotherapy. Therefore, implementing the recommended non-pharmacological treatments may reduce BAP.

Association between sleep state misperception and bedtime behavior in patients with chronic insomnia.

Previous studies on sleep state misperception have objectively evaluated sleep status in special environments using polysomnography. There is a paucity of data from studies that evaluated habitual sleep status in home environments. The present study aimed to investigate sleep state misperception in the home environment of patients with chronic insomnia using a lumbar-worn actigraphy to identify sleep habits associated with sleep state misperception severity. Thirty-one patients and 42 healthy volunteers were included in the insomnia and non-insomnia group, respectively. Participants recorded subjective assessments in sleep diaries, objective assessments with an actigraphy worn for 14 days, and self-assessments using questionnaires. Both groups had similar objective sleep ratings; however, insomnia group had significantly worse subjective ratings (total sleep time, wake after sleep onset, and sleep onset latency). A significant correlation was found between subjective and objective total sleep time scores in non-insomnia group but not in insomnia group. Insomnia group had earlier bedtimes, significantly longer bedtimes, and impaired daytime functioning (Sheehan Disability Scale score); additionally, they underestimated their total sleep time, particularly with earlier bedtimes and longer laying durations. Monitoring the sleep status and habits of individuals in home environments could be instrumental in identifying key points for targeted interventions on sleep hygiene and cognitive behavioral therapy for insomnia.

Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan.

Importance: Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. Objective: To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. Design, Setting, and Participants: This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. Exposures: Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. Main Outcomes and Measures: The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. Results: The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. Conclusions and Relevance: Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.

Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.

RATIONALE: The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue. OBJECTIVES: We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA. METHODS: This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed. RESULTS: Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia. CONCLUSIONS: Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed.

Development and validation of the Japanese version of the Bedtime Procrastination Scale (BPS-J).

BACKGROUND: The average sleep duration of Japanese people is shorter than that of people from other countries, and bedtime procrastination is suspected to be one of the factors contributing to this issue. This study aimed to develop and validate the Japanese version of the Bedtime Procrastination Scale (BPS-J). METHODS: The BPS-J was developed through procedures including the translation and back-translation of the scale, cognitive interviews with 100 participants who reported having experiences of being diagnosed with insufficient sleep syndrome (ISS) or receiving treatment for ISS using open-ended online questionnaires, and expert checking. To investigate the scale's validity and reliability, an online survey was conducted with daytime workers aged 20 - 65 years without a history of sleep disorders other than ISS. Half the participants were retested using the same survey after 14 days. Participants' responses to the Brief Self-Control Scale (BSCS), General Procrastination Scale (GPS), and Munich ChronoType Questionnaire (MCTQ), and data on sleep-related variables such as sleep duration on workdays and the days per week of fatigue or sleep loss, sex, and age, were collected. RESULTS: We analyzed data from 574 participants to assess scale validity. We then analyzed data from 280 participants to determine test-retest reliability. Confirmatory factor analyses revealed that the two-factor model without Item 2 was most suitable for the BPS-J, unlike other language versions. Regardless of the full-item model or the model with Item 2 eliminated, sufficient reliability and significant correlations with the BSCS, GPS, MCTQ, and sleep-related variables such as sleep duration per night on work days, days per week of feeling fatigued, and days per week of sleep loss were observed. Logistic and linear regressions showed that the relationships between the BPS-J, sleep-related variables, and MCTQ were maintained after adjusting for sex and age. CONCLUSION: The BPS-J had sufficient validity and reliability. Further, eliminating Item 2 from the original version of the BPS strengthened the ability to survey Japanese daytime workers.

Corrigendum: Decrease in social zeitgebers is associated with worsened delayed sleep-wake phase disorder: findings during the pandemic in Japan.

[This corrects the article DOI: 10.3389/fpsyt.2022.898600.].

Effects of Japanese policies and novel hypnotics on long-term prescriptions of hypnotics.

AIM: The current study aimed to examine the effect of Japanese policies for appropriate hypnotics use and novel hypnotics (e.g. melatonin receptor agonist and orexin receptor antagonist [ORA]) on long-term prescriptions of hypnotics. METHODS: This retrospective study was conducted using a large-scale health insurance claims database. Among subscribers prescribed hypnotics at least once between April 2005 and March 2021, those prescribed hypnotics for the first time after being included in the database in three periods (period 1: April 2012-March 2013; period 2: April 2016-March 2017; and period 3: April 2018-March 2019) were eligible. These were set considering the timing of the 2014 and 2018 medical fee revisions (2014 for polypharmacy of three or more hypnotics, 2018 for long-term prescription of benzodiazepine receptor agonists for >12 months). The duration of consecutive prescriptions of hypnotics over 12 months was evaluated. Factors associated with short-term prescriptions of hypnotics were also investigated. RESULTS: In total, 186 535 participants were newly prescribed hypnotics. The mean duration of prescriptions was 2.9 months, and 9.3% of participants were prescribed hypnotics for 12 months. Prescription periods were not associated with short-term prescriptions of hypnotics. ORA use was associated with short-term prescriptions of hypnotics (adjusted hazard ratio, 1.077 [95% confidence interval, 1.035-1.120]; P < 0.001), but melatonin receptor agonist use was not. CONCLUSION: Japanese policies had no statistically significant effect on long-term prescriptions of hypnotics. Although this study suggests initiating ORA for insomniacs as a candidate strategy to prevent long-term prescriptions of hypnotics, further research is necessary to draw conclusions.

Development and validation of the Japanese version of the Hyperarousal Scale.

BACKGROUND: The objectives of this study were to develop a Japanese version of the Hyperarousal Scale (HAS-J) and investigate its factor structure, reliability, and validity, as well as to calculate a cutoff score for the HAS-J and assess different levels of hyperarousal in insomnia patients and community dwellers. METHODS: We recruited 224 outpatients receiving insomnia treatment (56.3% women; mean age 51.7 ± 15.6 years) and 303 community dwellers aged 20 years or older (57.8% women; mean age 43.9 ± 15.2 years). Exploratory and confirmatory factor analysis was performed to examine the factor structure of the HAS-J. Cronbach's α and McDonald's ω were then used to test internal consistency. To examine the scale's validity, we determined correlations between the HAS-J and other indexes and compared HAS-J scores between insomnia patients and community dwellers. We also compared HAS-J scores between two community-dweller groups (normal and poor sleepers) and two insomnia patient groups (with and without alleviation after treatment). RESULTS: Following exploratory and confirmatory factor analysis, a 20-item measure emerged comprising three factors: "Introspectiveness and Reactivity," "Neuroticism," and "Insomnia." Confirmatory factor analysis showed a generally good fit for the model of the three-factor structure suggested by the exploratory factor analysis loadings (χ2 (163) = 327.423, (p <  0.001), CFI = 0.914, GFI = 0.872, AGFI = 0.835, RMSEA = 0.067). In insomnia patients, internal consistency indicated sufficient reliability of the HAS-J. Correlation analysis showed weak to moderate positive correlations of the HAS-J score with other indexes, indicating concurrent validity of the HAS-J. All HAS-J subscale scores were significantly higher in insomnia patients than in community dwellers. Additionally, the total score in patients with alleviation of insomnia was comparable to that in poor sleepers and significantly higher than that in normal sleepers. CONCLUSIONS: This study demonstrated the reliability and validity of the HAS-J, indicating that it is useful as a clinical scale of hyperarousal. The high level of hyperarousal in insomnia patients who were assessed to be in remission by the Insomnia Severity Index suggests a risk of insomnia recurrence in these patients.

Relationship between COVID-19-specific occupational stressors and mental distress in frontline and non-frontline staff.

This study investigated the difference in the severity of mental distress and factors contributing to mental distress in frontline and non-frontline healthcare professionals during the coronavirus disease (COVID-19) pandemic. A cross-sectional web-based survey of medical staff collected by snow-ball sampling was performed in Japan in October 2020 using the Kessler Psychological Distress Scale (K6) as an outcome measure for mental distress. Originally developed items asking about the degree of change in psychological and physical burdens, COVID-19-related fear, and experience of discrimination were obtained. The median score of the K6 was 7 in the frontline staff group (n = 86) and 6 in the non-frontline staff group (n = 504), without a statistically significant difference. Multiple regression analyses showed that among the participants, an increase in psychological burden and COVID-19-related fear was significantly associated with mental distress in both groups. Experience of discrimination was significantly associated with mental distress only in the frontline staff group. However, an increase in physical burden was significantly associated with mental distress only in the non-frontline staff group. The results indicate that the factors contributing to mental distress between frontline and non-frontline staff can be different, although the severity of mental distress is comparable between them.

Relationship among psychotic features, benzodiazepine receptor agonists, and rehospitalization in patients with electroconvulsive therapy-responsive major depressive disorder: A retrospective 2-year observational study.

AIM: It is controversial whether psychotic features are a risk factor for relapse in patients with electroconvulsive therapy-responsive major depressive disorder. A recent study reported that benzodiazepine receptor agonists reduce relapse of psychotic depression. As long-term use of these agonists may induce dependence, further research is required. We examined whether psychotic features are associated with rehospitalization in electroconvulsive therapy-responsive major depressive disorder patients. We also investigated whether taking benzodiazepine receptor agonists at the end of electro-convulsive therapy was associated with rehospitalization among patients with psychotic depression. METHODS: This study included 47 hospitalized patients (22 with psychotic depression, 25 with non-psychotic depression) who had responded to electroconvulsive therapy. Rehospitalization for major depressive episodes within two years from the last session was investigated. RESULTS: Twenty-three subjects (49%) were rehospitalized during the two-year follow-up. Kaplan-Meier analysis revealed no difference in rehospitalization between patients with psychotic and non-psychotic depression (Log-rank P = 0.87). Among the 22 responders to electroconvulsive therapy with psychotic depression, there was no difference in benzodiazepine receptor agonist use at the end of electroconvulsive therapy between the rehospitalization and non-rehospitalization groups. CONCLUSION: Our exploratory study found no difference in the benzodiazepine receptor agonists use at the end of electroconvulsive therapy between rehospitalization and non-rehospitalization groups in patients with electroconvulsive therapy-responsive psychotic depression. Thus, the relapse-preventing effect of these agonists in psychotic depression should be investigated in future randomized controlled trials. Further research is also needed to determine whether psychotic features are associated with rehospitalization in these patients.

Decrease in Social Zeitgebers Is Associated With Worsened Delayed Sleep-Wake Phase Disorder: Findings During the Pandemic in Japan.

Background: Delay in sleep-wake rhythms was observed in the general population during the coronavirus disease 2019 (COVID-19) pandemic. Patients with delayed sleep-wake phase disorder (DSWPD) may have also experienced exacerbation of symptoms, but no studies have investigated this topic. In this study, we aimed to retrospectively examine the changes in symptoms of outpatients with DSWPD both before and during the pandemic and to identify the factors associated with the exacerbation of sleep-wake rhythms. Methods: We included outpatients with DSWPD aged 16 years or older who visited the outpatient clinic due to sleep disorders between January and September 2020. Decreased social zeitgebers was defined as a reduction of 50% or more in the frequency of commuting to school or work during the COVID-19 pandemic. The severity of DSWPD was assessed using the clinical global impressions - severity of illness (CGI-S) at two points: before and during the pandemic. We defined the worsened, unchanged, and improved groups as those whose CGI-S scores worsened by at least one point, remained unchanged, and improved by at least one point, respectively. Multivariate logistic regression analysis was performed to determine the factors associated with worsened DSWPD symptoms. Results: Sixty patients with DSWPD were eligible for this study. Even before the pandemic, patients who were unemployed or did not attend school tended to show more severe DSWPD symptoms. During the pandemic, 27 patients belonged to the worsened group; 28 patients, unchanged group; and 5 patients, improved group. Decreased social zeitgebers (odds ratio [OR] = 6.668, 95% confidence interval [CI]: 1.653-26.891, p < 0.05) and comorbid mood disorders (OR = 8.876, 95% CI: 1.714-45.974, p < 0.05) showed independent significant associations with the worsening of DSWPD symptoms. Conclusions: During the pandemic, the symptoms of DSWPD tended to worsen. The obtained findings emphasize the importance of social zeitgebers, suggesting the need for external motivation in DSWPD treatment.

Associations Between the 2011 Great East Japan Earthquake and Tsunami and the Sleep and Mental Health of Japanese People: A 3-Wave Repeated Survey.

PURPOSE: Large-scale natural disasters have an enormous physical and mental impact, immediately after they occur, on people living near the central disaster areas. It is known that, in the early stages, a seismic disaster triggers high rates of symptoms for insomnia, depression, and anxiety. However, little information is available about their medium- to long-term clinical outcomes. In this study, we conducted a repeated cross-sectional nationwide questionnaire survey to clarify changes in the prevalence of insomnia and its background factors after the Great East Japan Earthquake, a huge earthquake with a moment magnitude of 9.0 that occurred on March 11, 2011. METHODS: We conducted a repeated cross-sectional survey in November 2009 (pre-earthquake, 1224 participants), July 2011 (4 months post-earthquake, 1259 participants), and August 2012 (18 months post-earthquake, 1289 participants) using stratified random sampling from 157 Japanese sites. RESULTS: Compared to 2009, the prevalence of insomnia statistically increased nationwide immediately post-disaster (11.7% vs 21.2%; p < 0.001) but significantly decreased in 2012 compared to immediately after the earthquake (10.6% vs 21.2%; p < 0.001). In 2011, insomnia was most frequent in the central disaster area. Multivariable logistic regression models demonstrated the association between the following factors and increased risk of insomnia: being a woman (odds ratio [OR] 1.48, 95% confidence interval [CI]: 1.00-2.19), being employed in 2009 (OR 1.74, 95% CI: 1.15-2.62), and being of younger age group (20-64 years) in 2011 (OR 1.64, 95% CI: 1.12-2.42) and 2012 (OR 2.50 95% CI: 1.47-4.23). Post-earthquake, the prevalence of insomnia symptoms in men increased, while the gender difference decreased and was no longer statistically significant. Additionally, insomnia was associated with psychological distress (scores ≥5 on the Kessler Psychological Distress Scale) in 2011 and 2012. CONCLUSION: This study demonstrated that the prevalence of insomnia was significantly higher after the earthquake. Moreover, individuals with insomnia were more likely to experience psychological distress after the earthquake that continued until 2012.

Training types associated with knowledge and experience in public health workers.

BACKGROUND: Training non-specialist workers in mental healthcare improves knowledge, attitude, confidence, and recognition of mental illnesses. However, still little information is available on which type of mental health training is important in the improvement of these capacities. METHODS: We studied web-based survey data of 495 public health workers to examine training types associated with knowledge and experience in supporting individuals with mental illness. Multivariable logistic regression analysis was conducted to evaluate the association between a lack of knowledge and experience (outcome) and mental health training (exposure). We fitted three regression models. Model 1 evaluated unadjusted associations. Model 2 adjusted for age and sex. Model 3 adjusted for age, sex, years of experience, mental health full-time worker status, and community population. Bias-corrected and accelerated bootstrap confidence intervals (CIs) were used. RESULTS: For all training types, the association between a lack of knowledge and experience and mental health training attenuated as the model developed. In Model 3, a lack of knowledge and experience was significantly associated with training in specific illness (OR, 0.54; 95% CI, 0.32-0.93) and screening and assessment (OR, 0.63; 95% CI, 0.39-0.99). Non-significant results were produced for training in counseling, psychosocial support, collaborative work, and law and regulation in Model 3. CONCLUSIONS: We believe that the present study provides meaningful information that training in specific illness and screening and assessment may lead to knowledge and experience of public health workers. Further studies should employ a longitudinal design and validated measurements.

Association of Subjective Quality and Quantity of Sleep with Quality of Life among a General Population.

This study aimed to determine whether both subjective sleep quality and sleep duration are directly associated with quality of life (QOL), as well as indirectly associated with QOL through insomnia symptoms. Individuals aged 20-69 years without mental illness (n = 9305) were enrolled in this web-based cross-sectional survey. The Short Form-8 was used to assess physical and mental QOL. We used the Pittsburgh Sleep Quality Index (PSQI) and extracted items related to subjective sleep quality and sleep duration. Insomnia symptoms were also extracted from the PSQI. The hypothesized models were tested using structural equation modeling. Worse sleep quality, but not shorter sleep duration, was related to worse physical QOL. Both worse sleep quality and shorter sleep duration were related to worse mental QOL. Insomnia symptoms mediated these relationships. Subgroup analyses revealed a U-shaped relationship between sleep duration and physical/mental QOL. However, the relationship between sleep quality and physical/mental QOL was consistent regardless of sleep duration. The results suggest that subjective sleep quality has a more coherent association with QOL than subjective sleep duration. Because of its high feasibility, a questionnaire on overall sleep quality could be a useful indicator in future epidemiological studies of strategies for improving QOL.

Psychological burden of attention-deficit/hyperactivity disorder traits on medical workers under the COVID-19 outbreak: a cross-sectional web-based questionnaire survey.

OBJECTIVES: There are numerous reports on the psychological burden of medical workers after the COVID-19 outbreak; however, no study has examined the influence of developmental characteristics on the mental health of medical workers. The objective of this study was to examine whether the developmental characteristics of medical workers are associated with anxiety and depression after the COVID-19 outbreak. DESIGN: We conducted an online cross-sectional questionnaire survey in October 2020. PARTICIPANTS AND SETTING: The data of 640 medical workers were analysed. The questionnaire included items on sociodemographic data, changes in their life after the COVID-19 outbreak and symptoms of depression, anxiety, attention-deficit/hyperactivity disorder (ADHD) traits and autism spectrum disorder traits. MAIN OUTCOMES: Depression symptoms were assessed by the Patient Health Questionnaire-9 and anxiety symptoms were assessed by the Generalised Anxiety Disorder-7. A series of hierarchical multiple regression analyses were performed to test the effects of developmental characteristics on depression and anxiety symptoms after controlling for sociodemographic factors and changes in participants' lives after the COVID-19 outbreak. RESULTS: Increases in physical and psychological burden were observed in 49.1% and 78.3% of the subjects, respectively. The results of a multiple regression analysis showed that ADHD traits were significantly associated with both depression (ß=0.390, p<0.001) and anxiety (ß=0.426, p<0.001). Autistic traits were significantly associated with depression (ß=0.069, p<0.05) but not anxiety. Increased physical and psychological burden, being female, medical workers other than physicians and nurses, fear of COVID-19 and experience of discrimination were also significantly associated with both depression and anxiety. CONCLUSION: Globally, the burden on medical workers increased. This study suggested that medical workers with higher ADHD traits may need special attention during the COVID-19 pandemic.

Pregabalin withdrawal in patients without psychiatric disorders taking a regular dose of pregabalin: A case series and literature review.

Pregabalin is a drug that can cause psychiatric symptoms via pregabalin withdrawal. Prior reports on pregabalin withdrawal have mainly focused on cases with pregabalin dependence or abuse, and little attention has been paid to patients who are prescribed regular doses of pregabalin. Herein, we report three cases of pregabalin withdrawal in patients without psychiatric disorders, taking regular doses of pregabalin, who developed psychiatric symptoms such as insomnia and anxiety after abrupt discontinuation of pregabalin. In addition, we conducted a systematic review of six case reports (previous studies) of pregabalin withdrawal under regular doses of pregabalin. Among the six cases, three patients had no comorbid mental or substance use disorders, the dose of pregabalin ranged from 150 to 600 mg/d, and the duration of pregabalin use ranged from a few weeks to many years. Of these six cases of pregabalin withdrawal, five had psychopathological symptoms, three had vegetative symptoms, and three had neurologic and physical complications. We concluded that since pregabalin withdrawal can occur even with regular doses and short-term use, clinicians must carefully reduce pregabalin doses when reducing or discontinuing treatment, paying close attention to withdrawal symptoms. Our case series sheds light on the scant evidence from previous research on physical dependence in patients who are taking regular doses of pregabalin. Furthermore, our cases were also valuable in demonstrating that pregabalin withdrawal can occur even after a relatively short period of 2 months.

Decreased activity in the reward network of chronic insomnia patients.

In modern society, many people have insomnia. Chronic insomnia has been noted as a risk factor for depression. However, there are few functional imaging studies of the brain on affective functions in chronic insomnia. This study aimed to investigate brain activities induced by emotional stimuli in chronic insomnia patients. Fifteen patients with primary insomnia and 30 age and gender matched healthy controls participated in this study. Both groups were presented images of fearful, happy, and neutral expressions consciously and non-consciously while undergoing MRI to compare the activity in regions of the brain responsible for emotions. Conscious presentation of the Happy-Neutral contrast showed significantly lower activation in the right orbitofrontal cortex of patients compared to healthy controls. The Happy-Neutral contrast presented in a non-conscious manner resulted in significantly lower activation of the ventral striatum, right insula, putamen, orbitofrontal cortex and ventral tegmental area in patients compared to healthy controls. Our findings revealed that responsiveness to positive emotional stimuli were decreased in insomniac patients. Specifically, brain networks associated with rewards and processing positive emotions showed decreased responsiveness to happy emotions especially for non-conscious image. The magnitude of activity in these areas also correlated with severity of insomnia, even after controlling for depression scale scores. These findings suggest that insomnia induces an affective functional disorder through an underlying mechanism of decreased sensitivity in the regions of the brain responsible for emotions and rewards to positive emotional stimuli.

The effect of short or long sleep duration on quality of life and depression: an internet-based survey in Japan.

BACKGROUND: To date, no previous studies have evaluated the relationship between sleep duration and quality of life (QOL) or depression in the general population after controlling for daytime sleepiness and sleep disturbances. METHODS: A web-based cross-sectional survey was conducted with 8698 subjects aged 20-69 years. We examined the relationships between weekday sleep duration and daytime sleepiness, sleep disturbance, QOL and depression, using the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (without the item for sleep duration), 8-item Short Form and Center for Epidemiological Studies Depression Scale (CES-D). RESULTS: Daytime sleepiness tended to increase in proportion to shorter weekday sleep durations. Sleep disturbances, physical and mental QOL, and CES-D scores were worse in both the shorter and longer sleep groups compared with the group with 7-8 h of sleep. Hierarchical logistic regression analyses revealed that short sleep duration but not long sleep duration was significantly associated with reduction of both physical and mental QOL, even after controlling for the presence of daytime sleepiness and sleep disturbance. Both short and long sleep duration were independently and significantly correlated with depression after controlling for daytime sleepiness; however, there was no statistically significant association after adjusting for the effects of sleep disturbance. CONCLUSIONS: The results suggested adverse effects of short sleep but not long sleep on both physical and mental QOL. In addition, the negative impact of specific types of sleep disturbance on depression may be greater than the impact of shortening of sleep duration.

Effectiveness of cognitive behavioral therapy for pharmacotherapy-resistant chronic insomnia: a multi-center randomized controlled trial in Japan.

OBJECTIVES: An insomnia characterized by nighttime symptoms and daytime impairment is common. GABA-A receptor agonist (GABAA-RA) treatment is often used, but long-term use is controversial due to the poor risk-benefit ratio resulting from drug dependence and potential cognitive impairment. This study evaluated the effectiveness of add-on cognitive behavioral therapy for insomnia (CBT-I) and GABAA-RA dose-tapering in patients with primary insomnia resistant to pharmacotherapy. METHODS: This randomized, multicenter, two-arm, parallel-group study compared CBT-I and treatment as usual (TAU) in patients with persistent primary insomnia despite GABAA-RA treatment. Screening was based on sleep diary entries, with ≥31-min sleep latency or wake after sleep onset, occurring ≥3 times in a week and total score of ≥8 on the Insomnia Severity Index (ISI). Primary outcome measures were severity of insomnia and GABAA-RA tapering rate. RESULTS: A total of 51 patients were randomized and 49 patients were analyzed (CBT-I; n = 23, TAU; n = 26). A mixed-effects repeated-measures model revealed significant improvement in insomnia symptoms (ISI score) during the post-intervention (PI) and follow-up (FU) periods in the CBT-I versus the TAU group (PI; 10.91 vs. 14.33, p < 0.05, FU; 10.17 vs. 14.34, p < 0.01). GABAA-RA tapering rate approached 30% during follow-up in the CBT-I group; no significant intergroup difference was observed. CONCLUSION: Add-on CBT-I improved insomnia symptoms that were unresponsive to GABAA-RA therapy. No effect on tapering rate was observed in this study. CBT-I may promote dose reduction by optimizing the protocol and duration of treatment. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000014297.