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Previous studies have reported inconsistent results about exogenous melatonin's sleep-promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta-analysis of double-blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep-related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose-response and meta-regression models were estimated to explore how time of administration, dose, and other treatment-related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose-response meta-analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta-regression models showed that insomnia status (ß = 0.50, p < 0.001) and time between treatment administration and the sleep episode (ß = -0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (ß = -0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.
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Melatonina , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios do Início e da Manutenção do Sono , Melatonina/administração & dosagem , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Relação Dose-Resposta a Droga , Sono/efeitos dos fármacosRESUMO
Risk is the probability of an adverse event. The proneness to take a risk and the risk taking behavior differ among the general population. Hypnotizability is a stable psychophysiological trait expressing the individual proneness to modify perception, memory and behavior following specific suggestions also in the ordinary state of consciousness. Some hypnotizability-related neurophysiological and behavioral correlates suggest that hypnotizability level, measured by standard scales classifying individuals as low (lows), medium (mediums) and high hypnotizable (highs) subjects, can be related to risk propensity and risk-taking. To study whether hypnotizability modulates risk propensity and behavior, we recruited healthy participants, classified through the Standford Hypnotic Susceptibility scale, form A, and compared lows' (n = 33), mediums' (n = 19) and highs'(n = 15) experiential and behavioral risk perception and propensity variables through the Domain-specific risk-taking scale and the Balloon Analogue Risk Task. MANOVA results indicated that different hypnotizability levels are not associated with different risky behavior and experience, except for higher expected financial benefits from risky behavior in lows. However, hypnotizability-related risk profiles were identified through correlational analyses. In fact, highs exhibited a negative association between risk perception and propensity to risk-taking, whereas mediums and lows displayed a positive association between risk propensity and expected benefit. In conclusion, the highs' profile indicates a more automatic behavior with respect to mediums and lows.
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Hipnose , Assunção de Riscos , Humanos , Hipnose/métodosRESUMO
Autism spectrum disorder (ASD) is characterized by multifactorial etiology and high heritability but can be challenging to be diagnosed, especially in cases presenting subthreshold symptoms with no cognitive or language impairment, which may not be identified until adulthood but may occur in family members of subjects with ASD. This study explores the possible correlation between a genomic imbalance and clinical phenotypes in a family case of a proband with ASD, with subjects presenting full-blown or subthreshold ASD and/or mood disorders. Clinical assessments were carried out by means of the Structured Clinical Interview for DSM-5 (SCID-5) disorders, Autism Spectrum Quotient (AQ), Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule Module 2 (ADOS-2), and Adult Autism Subthreshold Spectrum (AdAS Spectrum). The genetic evaluation included array comparative genomic hybridization (array-CGH). The proband was diagnosed with ASD and bipolar disorder type I (BD-I), her twin brothers with ASD and intellectual disability (ID), and her father and sister with BD type II (BD-II) and autism traits. The proband, her father, twin brothers, and older sister showed a microduplication of 350 kb in 20q11.21. In contrast, the proband's mother did not present the microduplication or any mental disorder. This study reports a microduplication that segregates with family members affected by ASD or autistic traits comorbid in some cases with bipolar disorder, and that has never been reported in healthy subjects. Among the genes harbored in this region, the TM9SF4 gene has been recently implicated in risk for ASD.
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The present study evaluates the effect of exogenous melatonin (exo-MEL) on sleep and circadian parameters in patients with bipolar disorder (BD) and delayed sleep-wake phase disorder (DSWPD). BD euthymic patients (n = 83, mean age = 45.13 ± 13.68, males 56%) were evaluated for chronotype (reduced Morningness-Eveningness Questionnaire [rMEQ]), sleep quality (Pittsburgh Sleep Quality Index), sleep and circadian parameters (actigraphic monitoring). Patients that fulfilled criteria for DSWPD (n = 25) were treated for three months with exo-MEL 2 mg administered approximately 4 h before the sleep onset time (SOT) actigraphically-determined at baseline. Sleep and circadian parameters at baseline (T0) and after the exo-MEL treatment (T1) were compared using paired Wilcoxon test. In patients that completed the treatment (n = 19), the rMEQ score increased between T0 (median = 8.0 [IQR = 7.0, 11.0]) and T1 (median = 13.5 [IQR = 9.3, 15.0], p-value = 0.006), the SOT was advanced between T0 (median = 00:55 [IQR = 00:25, 01:39] and T1 (median = 00:09 [IQR = 23:41, 01:04], p-value = 0.039), the sleep efficiency and total sleep time increased (T0: median = 84.4 [IQR = 81.3, 89.4]; T1 (median = 90.3 [IQR = 85.5, 92.9] %, p-value = 0.01, and T0: median = 7.20 [IQR = 6.15, 8.15]; T1: median = 7.7 [IQR = 7.0, 9.3] hours, p-value = 0.04, respectively). These results indicate that in BD with comorbid DSWPD, the self-reported chronotype, the sleep onset time, and sleep efficiency and duration were modified after a personalized treatment with exo-MEL, suggesting its potential efficacy in improving sleep patterns in BD. The absence of proper control groups and of treatment randomization constitute limitations of our study and further randomized controlled trials are required to confirm our results.
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Transtorno Bipolar , Melatonina , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Melatonina/farmacologia , Melatonina/uso terapêutico , Transtorno Bipolar/complicações , Transtorno Bipolar/tratamento farmacológico , Sono , Ritmo Circadiano , ComorbidadeRESUMO
OBJECTIVE: Although the association between chronotype and mood disorders has been consistently reported, conversely, attempts to measure the association between chronotype and anxiety symptoms have generated inconsistent results. We aimed at evaluating whether chronotype (assessed through subjective and objective measures) is associated with lifetime mood and panic-agoraphobic spectrum symptoms in healthy controls (HCs) and in patients with bipolar disorder (BD). METHODS: Overall, 173 subjects, patients with BD in euthymic phase (n = 76) and HC (n = 97), were evaluated through the reduced Morningness-Eveningness Questionnaire (rMEQ), actigraphy monitoring and mood and panic-agoraphobic spectrum self-report (MOODS-SR and PAS-SR). The discrepancy between objective (actigraphic-based) versus subjective (rMEQ-based) circadian typology was estimated through the Circadian Classification Discrepancy Index (CCDI). RESULTS: rMEQ-based evening chronotype (ET) was associated with higher scores in MOODS-SR depressive and rhythmicity and vegetative functions domains in HC and BD.Both ET and morning chronotypes (MT) were associated with higher PAS-SR scores in BD only. Actigraphic-based MT was associated with higher MOODS-SR depressive scores in HC. Likewise, the discrepancy between actigraphic-based and rMEQ-based circadian typology was associated with depressive symptoms in HC only. CONCLUSION: Self-reported ET was consistently associated with mood symptoms, while associations with panic-agoraphobic symptoms only emerged in BD and involved both extreme chronotypes. The discrepancy between the preferred circadian typology (rMEQ-based) and the actual one (actigraphic-based) could contribute to depressive symptoms in HC. These results pave the way for interventional studies targeting circadian typology in an attempt to prevent or treat mental health disorders.
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Transtorno Bipolar , Humanos , Transtorno Bipolar/complicações , Transtorno Bipolar/psicologia , Cronotipo , Transtornos do Humor , Ansiedade , Afeto , Inquéritos e Questionários , Ritmo Circadiano , SonoRESUMO
The present study aimed at exploring whether lifetime post-traumatic stress spectrum symptoms are associated with chronotype in patients with bipolar disorder (BD). Moreover, we explored whether the chronotype can moderate the potential associations between lifetime post-traumatic stress spectrum symptoms and rest-activity circadian and sleep-related parameters. A total of 74 BD patients were administered the Trauma and Loss Spectrum Self-Report (TALS-SR) lifetime version for lifetime post-traumatic stress spectrum symptoms, the Pittsburgh Sleep Quality Index (PSQI) for self-reported sleep quality, and the Reduced Morningness-Eveningness Questionnaire (rMEQ) to discriminate evening chronotypes (ETs), neither chronotype (NT), and morning chronotype (MT). Actigraphic monitoring was used to objectively evaluate sleep and circadian parameters. Patients classified as ET reported significantly higher scores in the re-experiencing domain, as well as poorer sleep quality, lower sleep efficiency, increased wake after sleep onset, and delayed mid-sleep point compared with both NT and MT (p-value ≤ 0.05). Moreover, ET presented significantly higher scores in the TALS-SR maladaptive coping domain than NT and lower relative amplitude than MT (p-value ≤ 0.05). Moreover, higher TALS-SR total symptomatic domains scores were significantly correlated with poor self-reported sleep quality. Regression analyses showed that the PSQI score maintained the association with the TALS total symptomatic domains scores after adjusting for potentially confounding factors (age and sex) and that no interaction effect was observed between the chronotype and the PSQI. Conclusions: This exploratory study suggests that patients with BD classified as ET showed significantly higher lifetime post-traumatic stress spectrum symptoms and more disrupted sleep and circadian rhythmicity with respect to other chronotypes. Moreover, poorer self-reported sleep quality was significantly associated with lifetime post-traumatic stress spectrum symptoms. Further studies are required to confirm our results and to evaluate whether targeting sleep disturbances and eveningness can mitigate post-traumatic stress symptoms in BD.
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Transtorno Bipolar , Distúrbios do Início e da Manutenção do Sono , Transtornos de Estresse Pós-Traumáticos , Humanos , Sono , Ritmo Circadiano , Inquéritos e QuestionáriosRESUMO
Adolescents' conflict between circadian rhythm and early school start time is more pronounced in evening chronotypes, who tend to reduce sleep duration during school days compensating during the free days by oversleeping (i.e., social jetlag). Cumulative weekly sleep debt may impair sport performance, which relies on physical and cognitive skills modulated by sleep. We hypothesized that chronotype predicts sport performance, and that it may interact with the day of the week. Moreover, given the role sleep plays in motor memory consolidation, we tested the hypothesis that school attendance, and the related chronic sleep deprivation, might be detrimental for participants in a training phase. Ninety-three adolescent male basketball players performed multiple free throw sessions (n = 7880) during both the school and holiday periods. Chronotype and its interaction with the day of the week significantly predicted shooting accuracy when attending school, but not on holidays. Evening types' performance gradually decreased from Monday to Friday. Participants with a more unstable performance (i.e., who did not complete the acquisition of the free throw motor scheme) worsened their accuracy when attending school. Our results suggest that the impact of chronotype and day of the week on sport performance is related to the presence of an externally imposed sleep/wake schedule and is consistent with evening types' increased likelihood of experiencing social jetlag. Possibly due to early school start time, attending school worsened the performance of participants in a training phase. Further investigations are required to assess whether reducing the mismatch between biological and social clocks might improve sport performance, along with other aspects of adolescents' life.
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Basquetebol , Ritmo Circadiano , Humanos , Masculino , Adolescente , Cronotipo , Sono , Síndrome do Jet Lag , Instituições Acadêmicas , Inquéritos e QuestionáriosRESUMO
The use of exogenous melatonin (exo-MEL) as a sleep-promoting drug has been under extensive debate due to the lack of consistency of its described effects. In this study, we conduct a systematic and comprehensive review of the literature on the chronobiotic, sleep-inducing, and overall sleep-promoting properties of exo-MEL. To this aim, we first describe the possible pharmacological mechanisms involved in the sleep-promoting properties and then report the corresponding effects of exo-MEL administration on clinical outcomes in: a) healthy subjects, b) circadian rhythm sleep disorders, c) primary insomnia. Timing of administration and doses of exo-MEL received particular attention in this work. The exo-MEL pharmacological effects are hereby interpreted in view of changes in the physiological properties and rhythmicity of endogenous melatonin. Finally, we discuss some translational implications for the personalized use of exo-MEL in the clinical practice.
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Melatonina , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Ritmo Circadiano , Sono/fisiologiaRESUMO
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease of presenile onset. A better characterization of neurodegenerative disorders has been sought by using tools such as genome-wide association studies (GWAS), where associations between single nucleotide polymorphisms (SNPs) and cognitive profiles could constitute predictive biomarkers for these diseases. However, in FTD, associations between genotypes and cognitive phenotypes are yet to be explored. Here, we evaluate a possible relationship between genetic variants and some cognitive functions in an FTD population. Methodology: A total of 47 SNPs in genes associated with neurodegenerative diseases were evaluated using the Sequenom MassARRAY platform along with their possible relationship with performance in neuropsychological tests in 105 Colombian patients diagnosed with FTD. Results and discussion: The SNPs rs429358 (APOE), rs1768208 (MOBP), and rs1411478 (STX6), were identified as risk factors for having a low cognitive performance in inhibitory control and phonological verbal fluency. Although the significance level was not enough to reach the corrected alpha for multiple comparison correction, our exploratory data may constitute a starting point for future studies of these SNPs and their relationship with cognitive performance in patients with a probable diagnosis of FTD. Further studies with an expansion of the sample size and a long-term design could help to explore the predictive nature of the potential associations we identified.
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Introduction: Older-age bipolar disorder (OABD) may involve neurocognitive decline and behavioral disturbances that could share features with the behavioral variant of frontotemporal dementia (bvFTD), making the differential diagnosis difficult in cases of suspected dementia. Objective: To compare the neuropsychological profile, brain morphometry, and structural connectivity patterns between patients diagnosed with bvFTD, patients classified as OABD with an early onset of the disease (EO-OABD), and healthy controls (HC). Methods: bvFTD patients (n = 25, age: 66 ± 7, female: 64%, disease duration: 6 ± 4 years), EO-OABD patients (n = 17, age: 65 ± 9, female: 71%, disease duration: 38 ± 8 years), and HC (n = 28, age: 62 ± 7, female: 64%) were evaluated through neuropsychological tests concerning attention, memory, executive function, praxis, and language. Brain morphometry was analyzed through surface-based morphometry (SBM), while structural brain connectivity was assessed through diffusion tensor imaging (DTI). Results: Both bvFTD and EO-OABD patients showed lower performance in neuropsychological tests of attention, verbal fluency, working memory, verbal memory, and praxis than HC. Comparisons between EO-OABD and bvFTD showed differences limited to cognitive flexibility delayed recall and intrusion errors in the memory test. SBM analysis demonstrated that several frontal, temporal, and parietal regions were altered in both bvFTD and EO-OABD compared to HC. In contrast, comparisons between bvFTD and EO-OABD evidenced differences exclusively in the right temporal pole and the left entorhinal cortex. DTI analysis showed alterations in association and projection fibers in both EO-OABD and bvFTD patients compared to HC. Commissural fibers were found to be particularly affected in EO-OABD. The middle cerebellar peduncle and the pontine crossing tract were exclusively altered in bvFTD. There were no significant differences in DTI analysis between EO-OABD and bvFTD. Discussion: EO-OABD and bvFTD may share an overlap in cognitive, brain morphometry, and structural connectivity profiles that could reflect common underlying mechanisms, even though the etiology of each disease can be different and multifactorial.
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RESUMEN INTRODUCCIÓN: Los pacientes con trastorno afectivo bipolar pueden presentar alteraciones cognoscitivas que en algunos casos tienen un curso progresivo, por lo cual se ha cuestionado si la evolución de esta enfermedad se asocia a demencia, particularmente aquellas pertenecientes al espectro de la degeneración lobar frontotemporal. En este contexto, discriminar si un paciente presenta una demencia secundaria a la enfermedad psiquiátrica de base o si cursa una enfermedad neurodegenerativa además del trastorno afectivo bipolar, es un desafío para el diagnóstico diferencial. OBJETIVO: Comparar los desempeños cognoscitivos en pacientes con trastorno afectivo bipolar, con veinte años o más de evolución de la enfermedad y pacientes con demencia frontotemporal variante conductual. MATERIALES Y MÉTODOS: Estudio exploratorio, descriptivo y transversal en una cohorte seleccionada de casos por método no probabilístico. Los datos se analizan por medio de estadísticos no paramétricos. RESULTADOS: Eespecto al grupo control (N:27), los pacientes con demencia frontotemporal (N:24) presentan desempeños significativamente bajos en memoria verbal, funciones ejecutivas, praxias visoconstruccionales y atención (p <0,01). El grupo de trastorno bipolar (N:17) tiene bajos desempeños en estos procesos, pero no presenta fenómenos patológicos significativos asociados a intrusiones y perseveraciones. Entre los grupos clínicos no se identifican diferencias significativas. CONCLUSIÓN: Aunque los grupos clínicos comparten el compromiso en los procesos cognoscitivos evaluados, los desempeños son más bajos en el grupo de demencia frontotemporal, lo que sugiere que en una enfermedad degenerativa de menor tiempo de evolución y aparición en etapa presenil el déficit cognitivo es mayor que en una enfermedad psiquiátrica crónica.
SUMMARY INTRODUCTION: Patients with Bipolar Disorder may present cognitive alterations that in some cases have a progressive course, whereby it has been questioned if the evolution of this disease is associated with dementia, in particular those that belong to the spectrum of frontotemporal lobar degeneration. Thereby, discriminate if a patient has a dementia secondary to the underlying psychiatric illness or if the patient presents a neurode-generative disease besides the bipolar disorder is a challenge for the differential diagnosis. OBJECTIVE: To compare the cognitive performance in a sample of patients with Bipolar Disorder and twenty years or more of disease progression, and patients with behavioral variant of frontotemporal dementia. MATERIALS AND METHODS: Exploratory, descriptive and transversal study in a cohort of cases selected with a non probabilistic method. Dates are compared through non parametric statistics. RESULTS: Relative to Control group (N:27), Frontotemporal Dementia Patients (N:24) have significantly lower performances in verbal memory, executive functions, visoconstructional praxis and attention tasks (p <0,01). Bipolar Disorder group (N:17) has lower performances in this processes but don't present pathological markers such as intrusions and perseverative responses. There are no significant differences when comparing between clinical groups. CONCLUSION: Although clinical groups share the compromise in most of the cognitive process evaluated, the performances are lower in Frontotemporal dementia group, which suggests that in a degenerative disease of less evolution time and onset in presenile stage, the cognitive deficit is greater than in a chronic psychiatric illness.