RESUMEN
Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. We report results from the first two randomised, double-blind clinical studies of daridorexant in Japanese subjects. In the Phase 1 study, daridorexant (10, 25, 50 mg) or placebo were administered in the morning for 4 days in 24 young (mean age 26.9 years) and 24 older (mean age 69.7 years) healthy Japanese adults. Daridorexant reached a peak plasma concentration within 1.0 h across every dose and age group. For all doses, the mean plasma concentration of daridorexant showed a similar change between the age groups. Exposure parameters increased dose-dependently with minimal/no accumulation upon repeated dosing. The terminal half-life was ~8 h. In the Phase 2, four-period, four-way crossover study, 47 Japanese subjects (mean age 50.4 years) with insomnia disorder were randomised to receive four treatments (daridorexant 10, 25, 50 mg, placebo) during four treatment periods, each consisting of two treatment nights (5-12 day washout between treatment periods). Subjects continued their fourth treatment for 12 further days. A statistically significant dose-response relationship (multiple-comparison procedure-modelling, p < 0.0001) was found in the reduction of polysomnography-measured wake after sleep onset (WASO; primary endpoint) and latency to persistent sleep (secondary endpoint) from baseline to days 1/2. Statistically significant dose-response relationships were also observed for secondary subjective endpoints from baseline to days 1/2 (sWASO, latency to sleep onset). All daridorexant doses were well tolerated, with no treatment discontinuations and no next-morning residual effects. These results supported further investigation of daridorexant in Japanese patients with insomnia disorder.
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Previously, insomnia and adverse lifestyle were prevalent among truck drivers, but the association between the two remains unknown in this particular occupational cohort. This study aimed to examine the relationship between insomnia and lifestyle-related diseases among truck drivers. We investigated 875 male truck drivers of the Japan Truck Association, Akita branch, as of July 2020. The definition of insomnia was based on the International Classification of Sleep Disorders, Third Edition (ICSD-3). Data from a self-administered questionnaire were merged with health records and health insurance claims data of 2020. In total, 40.1% had either one of the lifestyle-related diseases including hypertension (29.7%), diabetes mellitus (11.7%), and dyslipidemia (24.8%), whereas according to ICSD-3, 13.2% had insomnia. Multivariate logistic regression models demonstrated that individuals with insomnia had approximately 2-fold increased risk of having at least one lifestyle-related disease (p < 0.001), hypertension (p = 0.0027), diabetes mellitus (p = 0.0654) and dyslipidemia (p < 0.001). Occupational characteristics including daily driving hours, driving distance, and travel days were not associated with any lifestyle-related diseases except for an association between short-haul and at least one disease. In conclusion, insomnia is significantly associated with increased risks of lifestyle-related diseases among male truck drivers in Japan.
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Conducción de Automóvil , Diabetes Mellitus , Hipertensión , Enfermedades Profesionales , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Masculino , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Pueblos del Este de Asia , Vehículos a Motor , Estilo de Vida , Hipertensión/complicaciones , Hipertensión/epidemiologíaRESUMEN
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.
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Hipnóticos y Sedantes , Humanos , Benzodiazepinas/farmacología , Prescripciones de Medicamentos , Hipnóticos y Sedantes/farmacología , Antagonistas de los Receptores de Orexina , Receptores de Melatonina , Estudios Retrospectivos , Japón , Política de SaludRESUMEN
BACKGROUND: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. METHODS: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. RESULTS: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. CONCLUSIONS: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.
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Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Zolpidem , Accidentes por Caídas , Análisis de Costo-Efectividad , Japón , Vehículos a Motor , Lugar de Trabajo , Análisis Costo-BeneficioRESUMEN
We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which the two drugs used were specified (i.e., aripiprazole, aripiprazole once monthly, aripiprazole+lamotrigine, aripiprazole+valproate, asenapine, carbamazepine, lamotrigine, lamotrigine+valproate, lithium, lithium+oxcarbazepine, lithium+valproate, olanzapine, paliperidone, quetiapine, risperidone long-acting injection, valproate, and placebo). The second included studies on second-generation antipsychotic combination therapies (SGAs) (i.e., aripiprazole, lurasidone, olanzapine, quetiapine, and ziprasidone) with lithium or valproate (LIT/VAL) compared with placebo with LIT/VAL. Outcomes were recurrence/relapse rate of any mood episode (RR-any, primary), depressive episode (RR-dep) and manic/hypomanic/mixed episode (RR-mania), discontinuation, mortality, and individual adverse events. Risk ratios and 95% credible interval were calculated. Forty-one randomized controlled trials were identified (n = 9821; mean study duration, 70.5 ± 36.6 weeks; percent female, 54.1%; mean age, 40.7 years). All active treatments other than carbamazepine, lamotrigine+valproate (no data) and paliperidone outperformed the placebo for RR-any. Aripiprazole+valproate, lamotrigine, lamotrigine+valproate, lithium, olanzapine, and quetiapine outperformed placebo for RR-dep. All active treatments, other than aripiprazole+valproate, carbamazepine, lamotrigine, and lamotrigine+valproate, outperformed placebo for RR-mania. Asenapine, lithium, olanzapine, quetiapine, and valproate outperformed placebo for all-cause discontinuation. All SGAs+LIT/VALs other than olanzapine+LIT/VAL outperformed placebo+LIT/VAL for RR-any. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-dep. Aripiprazole+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-mania. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for all-cause discontinuation. Treatment efficacy, tolerability, and safety profiles differed among treatments.
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Antipsicóticos , Trastorno Bipolar , Adulto , Antimaníacos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Femenino , Humanos , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33-0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17-0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28-0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36-0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23-0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36-0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29-0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35-0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29-0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40-0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18-0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.
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Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Inducción de Remisión , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/uso terapéutico , Ensayos Clínicos Controlados como Asunto , Depresión/tratamiento farmacológico , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
OBJECTIVE: Clozapine may cause serious side effects despite benefits in patients with schizophrenia. Thus, an accurate understanding of the side-effect profile of clozapine is extremely important in the management of its administration to patients with schizophrenia. Our aim was to validate the relationship between clozapine exposure and appendicitis onset in patients with schizophrenia. METHODS: In this study, we retrospectively compared the incidence and cumulative incidence of appendicitis in patients with schizophrenia with and without a history of clozapine exposure. Among the patients with schizophrenia who visited our hospital between June 2009 and August 2021, we extracted those with a history of clozapine treatment. Patients with a history of taking clozapine were defined as the clozapine exposure group, while the others were defined as the clozapine non-exposure group. Patients with a history of appendectomy before their initial visit to our hospital or with a history of clozapine use at other hospitals were excluded. RESULTS: There were 65 patients in the clozapine exposure group and 400 patients in the clozapine non-exposure group who met the inclusion criteria. The exposure group exhibited a remarkably higher incidence of appendicitis during the observation period than the non-exposure group (863 cases vs. 124 cases per 100,000 person-years). In particular, if limited to the period of clozapine exposure, the incidence of appendicitis is extremely high, at 2,086 cases per 100,000 person-years. Moreover, multivariable analysis showed that clozapine exposure was an independent factor contributing to the onset of appendicitis. CONCLUSIONS: Clozapine exposure is associated with appendicitis onset in patients with schizophrenia.
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Antipsicóticos , Apendicitis , Clozapina , Esquizofrenia , Humanos , Clozapina/efectos adversos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/epidemiología , Esquizofrenia/inducido químicamente , Estudios Retrospectivos , Antipsicóticos/efectos adversos , Apendicitis/inducido químicamente , Apendicitis/epidemiología , Apendicitis/tratamiento farmacológicoRESUMEN
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.
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Trastornos del Inicio y del Mantenimiento del Sueño , Adulto , Anciano , Nivel de Alerta , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Psicometría , Reproducibilidad de los Resultados , Trastornos del Inicio y del Mantenimiento del Sueño/diagnóstico , Trastornos del Inicio y del Mantenimiento del Sueño/terapiaRESUMEN
BACKGROUND: This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups. METHODS: We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months. RESULTS: We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54-0.70, 5) for any mood episode, 0.72 (0.60-0.87, 13) for depressive episodes, and 0.45 (0.36-0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61-0.82, 6). CONCLUSIONS: Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.
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Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Resultado del TratamientoRESUMEN
OBJECTIVES: A systematic review and meta-analysis of double-blind, randomized placebo-controlled trials were conducted to examine how soon an increase in recurrence risk could be observed among bipolar I disorder (BDI) patients who were clinically stable with the combination therapy of mood stabilizers with second-generation antipsychotics (SGA+MS) treatment following second-generation antipsychotics discontinuation (i.e., MS alone) compared with SGA+MS maintenance. METHODS: Embase, PubMed, and CENTRAL databases were used for systematic literature searches until May/22/2020. The primary outcome was the recurrence rate of any mood episode at 6 months. The secondary outcomes were the recurrence rates of manic/hypomanic/mixed and depressive episodes and all-cause discontinuation at 6 months. The recurrence rates at 1, 2, 3, 9, and 12 months were also investigated. RESULTS: Eight studies (mean study duration = 58.25 ± 33.63 weeks) were identified (SGA+MS group [n = 1,456: 3 aripiprazole+MS studies, 1 lurasidone+MS study, 1 olanzapine+MS study, 2 quetiapine+MS studies, 1 ziprasidone+MS study] and placebo+MS group [n = 1,476]). Pooled SGA+MS exhibited lower recurrence rates of any mood episode, manic/hypomanic/mixed episodes, and depressive episodes as well as reduced all-cause discontinuation at every observational point. The risk ratios (95% confidence interval) of the recurrence rate at 6 months were 0.51 (0.39-0.86) for any mood episode, 0.42 (0.30-0.59) for manic/hypomanic/mixed episodes, and 0.39 (0.28-0.54) for depressive episodes. The RR for all-cause discontinuation was 0.67 (0.50-0.89). Both aripiprazole+MS and quetiapine+MS outperformed placebo+MS in the recurrence of any mood, manic/hypomanic/mixed, and depressive episodes at 6 months. CONCLUSIONS: SGA+MS prevented recurrence for up to 12 months for BDI compared with placebo+MS.
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Antipsicóticos , Trastorno Bipolar , Antimaníacos/uso terapéutico , Antipsicóticos/uso terapéutico , Aripiprazol/uso terapéutico , Trastorno Bipolar/inducido químicamente , Trastorno Bipolar/tratamiento farmacológico , Humanos , Fumarato de Quetiapina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Major depressive disorder (MDD) is highly prevalent in Japan and frequently accompanied by insomnia that may persist even with MDD remission. Hypnotics are used for the pharmacological treatment of insomnia, but their influence on MDD recurrence or residual insomnia following MDD remission is unclear. This retrospective, longitudinal, cohort study utilized a large Japanese health insurance claims database to investigate patterns of hypnotic prescriptions among patients with MDD, and the influence of hypnotic prescription pattern on MDD recurrence. METHODS: Eligible patients (20-56 years) were those registered in the Japan Medical Data Center database between 1 January 2005 and 31 December 2018, and prescribed antidepressant and hypnotic therapy after being diagnosed with MDD. Patients who had ceased antidepressant therapy for > 180 days were followed for 1 year to evaluate depression recurrence, as assessed using Kaplan-Meier estimates. Logistic regression modelling was used to analyze the effect of hypnotic prescription pattern on MDD recurrence. RESULTS: Of the 179,174 patients diagnosed with MDD who initiated antidepressant treatment between 1 January 2006 and 30 June 2017, complete prescription information was available for 2946 eligible patients who had been prescribed hypnotics. More patients were prescribed hypnotic monotherapy (70.8%) than combination therapy (29.2%). The most prescribed therapies were benzodiazepine monotherapy (26.2%), non-benzodiazepine monotherapy (28.9%), and combination therapy with two drugs (21.1%). Among patients prescribed multiple hypnotics, concomitant prescriptions for anxiolytics, antipsychotics, mood stabilizers and sedative antidepressants were more common. The 1-year recurrence rate for MDD was approximately 20%, irrespective of hypnotic mono- versus combination therapy or class of hypnotic therapy. Being a spouse (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03-2.02) or other family member (OR, 1.46, 95% CI, 0.99-2.16) of the insured individual, or being prescribed a sedative antidepressant (OR, 1.50, 95% CI, 1.24-1.82) conferred higher odds of MDD recurrence within 1 year of completing antidepressant therapy. CONCLUSIONS: Benzodiazepines are the most prescribed hypnotic among Japanese patients with MDD, though combination hypnotic therapy is routinely prescribed. Hypnotic prescription pattern does not appear to influence real-world MDD recurrence, though hypnotics should be appropriately prescribed given class differences in efficacy and safety.
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Trastorno Depresivo Mayor , Trastornos del Inicio y del Mantenimiento del Sueño , Estudios de Cohortes , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Hipnóticos y Sedantes/uso terapéutico , Seguro de Salud , Japón , Estudios Retrospectivos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológicoRESUMEN
Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.
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Trastornos de Ansiedad/terapia , Benzodiazepinas/administración & dosificación , Terapia Cognitivo-Conductual , Evaluación de Resultado en la Atención de Salud , Trastornos de Ansiedad/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: We aimed to estimate the prevalence of depressive symptoms as well as suicide-related ideation among Japanese university students during the stay-home order necessitated by the coronavirus disease 2019 pandemic in Japan, and offer evidence in support of future intervention to depression and suicide prevention strategies among college and university students. METHODS: The data for this cross-sectional study were derived from the Student Mental Health Survey conducted from May 20 to June 16, 2020 at a national university in Akita prefecture. Among the 5111 students recruited, 2712 participated in this study (response rate, 53%; mean age ± standard deviation, 20.5 ±3.5 years; men, 53.8%). Depressive symptoms were identified by using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: The prevalence of moderate depressive symptoms based on a PHQ-9 score ≥10 and suicide-related ideation based on question 9 of PHQ-9 ≥1, which encompasses thoughts of both suicide and self-harm, was 11.7% and 6.7%, respectively. Multivariable logistic regression analyses showed that risk factors for depression included being a woman, smoking, alcohol consumption, and social network communication using either video or voice. For suicide-related ideation, alcohol consumption was the only risk factor. Exercise and having someone to consult about worries were associated with decreased risk of both depressive symptoms and suicide-related ideation. CONCLUSIONS: Negative lifestyles of smoking and drinking, and being a woman, may be important risk factors for depressive symptoms, whereas exercise and having someone to consult about worries may be protective factors.
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COVID-19/psicología , Depresión/epidemiología , Estudiantes/psicología , Ideación Suicida , Adolescente , Consumo de Bebidas Alcohólicas , Estudios Transversales , Femenino , Humanos , Japón/epidemiología , Modelos Logísticos , Masculino , Análisis Multivariante , Pandemias , Factores de Riesgo , Fumar , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: The exact recurrence rate of bipolar disorder in patients receiving lithium maintenance phase treatment and the modifiers associated with recurrence are still unknown. METHODS: We searched Embase, PubMed, and CENTRAL from inception until April 28, 2020. Outcomes included recurrence rate of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes; all-cause discontinuation rate; and discontinuation rate due to adverse events. A random-effects model, single-group summary meta-analysis was conducted. A meta-regression analysis to examine whether the modifiers (total number of patients, %female, mean age, duration of study, duration of preliminary phase, publication year, bipolar disorder type, mood status at recruitment, presence of a placebo arm, sponsorship, enrichment design, number of treatment arms, and risk of bias for blinding or randomization) were associated with the event rate of the outcomes was also performed. RESULTS: We identified 21 randomized trials (n = 1,415; mean study duration, 78.40 ± 32.10 weeks; %female, 54.85%; mean age, 43.47 ± 4.88 years). The event rates (95% confidence interval [CI]) were as follows: recurrence of any mood episode, 39.8% (32.8%, 47.1%); depressive episodes, 25.6% (18.8%, 34.0%); manic/hypomanic/mixed episodes, 18.5% (13.7%, 24.7%); all-cause discontinuation rate, 67.0% (57.2%, 75.5%); and discontinuation rate due to adverse events, 8.7% (5.1%, 14.7%). After adjusting for multiple testing, our meta-regression analysis showed association only between the all-cause discontinuation rate and presence of a placebo arm. CONCLUSIONS: The recurrence rate of depressive episodes seemed to be higher than the recurrence rate of manic/hypomanic/mixed episodes. The all-cause discontinuation rate was high. However, the studies included in our meta-analysis were of short duration.
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Afecto/efectos de los fármacos , Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Adulto , Antimaníacos/efectos adversos , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Femenino , Humanos , Compuestos de Litio/efectos adversos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: Clinical evidence is required about the long-term efficacy and safety of melatonin treatment for sleep problems in children with neurodevelopmental disorders (NDDs) who underwent adequate sleep hygiene interventions. METHODS: We conducted a 26-week, multicenter, collaborative, uncontrolled, open-label, phase III clinical trial of melatonin granules in children 6 to 15 years of age who had NDDs and sleep problems. The study consisted of the 2-week screening phase, the 26-week medication phases I and II, and the 2-week follow-up phase. Children received 1, 2, or 4 mg melatonin granules orally in the medication phases. Variables of sleep status including sleep onset latency (SOL), aberrant behaviors listed on the Aberrant Behavior Check List-Japanese version (ABC-J), and safety were examined. The primary endpoint was SOL in the medication phase I. RESULTS: Between June 2016 and July 2018, 99 children (80 males and 19 females, 10.4 years in mean age) were enrolled at 17 medical institutions in Japan-74, 60, 22, 9, 6, and 1 of whom had autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, motor disorders, specific learning disorder, and communication disorders, respectively, at baseline. Fifteen children received the maximal dose of 4 mg among the prespecified dose levels. SOL recorded with the electronic sleep diary shortened significantly (mean ± standard deviation [SD], - 36.7 ± 46.1 min; 95% confidence interval [CI], - 45.9 to - 27.5; P < 0.0001) in the medication phase I from baseline, and the SOL-shortening effect of melatonin persisted in the medication phase II and the follow-up phase. Temper upon wakening and sleepiness after awakening improved significantly (P < 0.0001 each) in the medication phase I from baseline and persisted in the follow-up phase. The following subscales of the ABC-J improved significantly: stereotypic behavior (P = 0.0322) in the medication phase I; and irritability, hyperactivity, and inappropriate speech (P < 0.0001) in the medication phase II. Treatment-emergent adverse events did not occur subsequent to week 16 after medication onset, and NDDs did not deteriorate in the follow-up phase. CONCLUSIONS: Long-term melatonin treatment in combination with adequate sleep hygiene interventions may afford clinical benefits to children with NDDs and potentially elevates their well-being. TRIAL REGISTRATION: ClinicalTrils.gov , NCT02757066 . Registered April 27, 2016.
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Trastorno del Espectro Autista , Melatonina , Trastornos del Neurodesarrollo , Trastornos del Sueño-Vigilia , Adolescente , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/tratamiento farmacológico , Niño , Femenino , Humanos , Japón , Masculino , Melatonina/uso terapéutico , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/tratamiento farmacológico , Sueño , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/tratamiento farmacológicoRESUMEN
Delayed sleep-wake phase disorder (DSWPD) is a subtype of circadian rhythm sleep-wake disorders, and is characterized by an inability to fall asleep until late at night and wake up at a socially acceptable time in the morning. The study aim was to identify low-frequency nonsense and missense variants that are associated with DSWPD. Candidate variants in circadian rhythm-related genes were extracted by integration of genetic variation databases and in silico assessment. We narrowed down the candidates to six variants. To examine whether the six variants are associated with DSWPD, we performed an association study in 236 Japanese patients with DSWPD and 1436 controls. A low-frequency missense variant (p.Val1205Met) in PER2 showed a significant association with DSWPD (2.5% in cases and 1.1% in controls, P = 0.026, odds ratio (OR) = 2.32). The variant was also associated with idiopathic hypersomnia known to have a tendency toward phase delay (P = 0.038, OR = 2.07). PER2 forms a heterodimer with CRY, and the heterodimer plays an important role in the regulation of circadian rhythms. Val1205 is located in the CRY-binding domain of PER2 and was hypothesized to interact with CRY. The p.Val1205Met substitution could be a potential genetic marker for DSWPD.
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Pueblo Asiatico/genética , Variación Genética/genética , Mutación Missense/genética , Proteínas Circadianas Period/genética , Trastornos del Sueño del Ritmo Circadiano/genética , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes/genética , HumanosRESUMEN
BACKGROUND: This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed. METHODS: The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose). RESULTS: We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50). CONCLUSIONS: Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d.
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Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Quimioterapia Combinada , Evaluación de Resultado en la Atención de Salud , Quinolonas/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Serotoninérgicos/farmacología , Tiofenos/farmacología , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Humanos , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Serotoninérgicos/administración & dosificación , Serotoninérgicos/efectos adversos , Tiofenos/administración & dosificación , Tiofenos/efectos adversosRESUMEN
BACKGROUND: Discontinuation of antipsychotics predisposes patients with remitted/stable first-episode psychosis (FEP) to a higher risk of relapse, but it remains unclear how long discontinuation increases the relapse rate in these patients compared with maintenance. METHODS: This meta-analysis of randomized controlled trials (RCTs) compared relapse rates in FEP patients between antipsychotic treatment discontinuation and maintenance groups at 1, 2, 3, 6, 9, 12 (primary), and 18-24 months. The risk ratio (RR) and numbers needed to treat/harm (NNT/NNH) were calculated using a random-effects model. RESULTS: Ten RCTs were identified (n = 776; mean study duration, 18.6 ± 6.0 months). The antipsychotics were discontinued abruptly in four RCTs (which reported data only at 12 months) and after tapering off gradually over several months (mean length, 3 months) in six RCTs. Compared with the discontinuation group, the maintenance group experienced significantly fewer relapses at all time points except 1 month [RR (NNT): 2 months, 0.49 (13); 3 months, 0.46 (9); 6 months, 0.55 (6); 9 months, 0.48 (3); 12 months, 0.47 (3); and 18-24 months, 0.57 (4)]. The maintenance group was associated with higher discontinuation due to adverse events (RR, 2.61; NNH, not significant). CONCLUSIONS: Maintaining antipsychotic treatment prevented relapse for up to 24 months in FEP patients. Discontinuation of antipsychotics for ⩾2 months significantly increased the risk of relapse. However, 45.7% of patients who discontinued antipsychotics for 12 months (39.4% after 18-24 months) did not experience a relapse.
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Antipsicóticos/administración & dosificación , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Polifarmacia , Psicotrópicos , Humanos , Anciano , Japón , Psicotrópicos/uso terapéutico , Masculino , Femenino , Anciano de 80 o más Años , Política de Salud , Pueblos del Este de AsiaRESUMEN
Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.