Sedative and hypnotic effects of the saponins from a traditional edible plant Liriope spicata Lour. in PCPA-induced insomnia mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Liriope spicata Lour., a species listed in the catalogue of 'Medicinal and Edible Homologous Species', is traditionally used for the treatment of fatigue, restlessness, insomnia and constipation. AIM OF THE STUDY: This study is aimed to evaluate the sedative and hypnotic effect of the saponins from a natural plant L. spicata Lour. in vivo. MATERIALS AND METHODS: The total saponin (LSTS) and purified saponin (LSPS) were extracted from L. spicata, followed by a thorough analysis of their major components using the HPLC-MS. Subsequently, the therapeutic efficacy of LSTS and LSPS was evaluated by the improvement of anxiety and depression behaviors of the PCPA-induced mice. RESULTS: LSTS and LSPS exhibited similar saponin compositions but differ in their composition ratios, with liriopesides-type saponins accounting for a larger proportion in LSTS. Studies demonstrated that both LSTS and LSPS can extend sleep duration and immobility time, while reducing sleep latency in PCPA-induced mice. However, there was no significant difference in weight change among the various mice groups. Elisa results indicated that the LSTS and LSPS could decrease levels of NE, DA, IL-6, and elevate the levels of 5-HT, NO, PGD2 and TNF-α in mice plasma. LSTS enhanced the expression of neurotransmitter receptors, while LSPS exhibited a more pronounced effect in regulating the expression of inflammatory factors. In conclusion, the saponins derived from L. spicata might hold promise as ingredients for developing health foods with sedative and hypnotic effects, potentially related to the modulation of serotonergic and GABAAergic neuron expression, as well as immunomodulatory process.

Zhumian Granules improves PCPA-induced insomnia by regulating the expression level of neurotransmitters and reducing neuronal apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep problems, according to Traditional Chinese medicine (TCM) philosophy, are attributed to the imbalance between yin and yang. Zhumian Granules, also known as Sleep-aid Granules or ZG, are a traditional Chinese herbal remedy specifically designed to alleviate insomnia. This formula consists of many components, including Wu Wei Zi (Schisandrae Chinensis Fructus), Suan Zao Ren (Ziziphi Spinosae Semen), and other medicinal plants. According to the pharmacology of Traditional Chinese Medicine (TCM), Wu Wei Zi and Suan Zao Ren have the ability to relax the mind and promote sleep. When taken together, they may balance the opposing forces of yin and yang. Therefore, ZG may potentially be used as a therapeutic treatment for insomnia. AIM OF THE STUDY: This research was specifically developed to establish a strong empirical basis for the subsequent advancement and utilization of ZG in the management of insomnia. This research aimed to gather empirical data to support the effectiveness of ZG, thereby providing useful insights into its potential therapeutic advantages for persons with insomnia. MATERIALS AND METHODS: This study utilized Zhumian Granules (ZG), a traditional Chinese herbal decoction, to examine its sedative and hypnotic effects on mice with PCPA-induced insomnia. The effects were assessed using the pentobarbital-induced sleep test (PIST), Morris water maze test (MWM), and autonomic activity test. The levels of neurotransmitters in each group of mice were evaluated using UPLC-QQQ-MS. The impact of ZG on the quantity and structure of hippocampal neurons was seen in brain tissue slices using immunofluorescence labeling. RESULTS: ZG was shown to possess active sedative properties, effectively lowering the distance of movement and lengthening the duration of sleep. ZG mitigated the sleeplessness effects of PCPA by elevating the levels of 5-hydroxytryptamine (5-HT), 4-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid (5-HIAA), while reducing the levels of dopamine (DA) and norepinephrine (NE), as well as decreasing neuronal death. CONCLUSIONS: This research confirmed the sedative and hypnotic properties of ZG and elucidated its probable mechanism involving neurotransmitters.

[Systematic review and Meta-analysis of efficacy and safety of Shumian Capsules in treatment of insomnia].

This study aims to assess the safety and efficacy of Shumian Capsules in the treatment of insomnia. Randomized controlled trial(RCT) about Shumian Capsules for insomnia were retrieved from databases. RevMan 5.4 was used for statistical analysis. A total of 23 articles were included, involving 2 621 patients. Meta-analysis showed that Shumian Capsules had advantages in the treatment of insomnia(RR=1.07, 95%CI[1.03, 1.10], P=0.000 2) and insomnia with depression(RR=1.13, 95%CI[1.02, 1.25], P=0.02) in terms of total response rate. Shumian Capsules had advantages in the treatment of insomnia(MD=-0.75, 95%CI[-1.33,-0.17], P=0.01) and insomnia with depression(MD=-2.51, 95%CI[-2.96,-2.06], P<0.000 01) in terms of PSQI score. The incidence of adverse events in the Shumian Capsules(RR=0.33, 95%CI[0.24, 0.46], P<0.000 01) and Shumian Capsules + conventional western medicine(RR=0.71, 95%CI[0.54, 0.95], P=0.02) was lower than that in the conventional wes-tern medicine alone. In addition, Shumian Capsules had an advantage in treating insomnia complicated with depression in terms of HAMD score(P<0.000 1) and reducing the serum levels of 5-HT, TSH, T3, and T4 in insomnia patients(P<0.05). The quality of evidence was mostly medium or low. The studies demonstrate that Shumian Capsules is effective and safe for treating insomnia, which may be related to the mechanism of lowering the levels of 5-HT, TSH, T3, and T4 in the serum. In view of the quality of evidence, the application of Shumian Capsules should be considered after comprehensive evaluation in clinical practice.

Cannabidiol Exerts Sedative and Hypnotic Effects in Normal and Insomnia Model Mice Through Activation of 5-HT1A Receptor.

Cannabis sativa has been used for improving sleep for long history. Cannabidiol (CBD) has drown much attention as a non-addictive psychoactive component in Cannabis sativa extract. However, the effects of CBD on sleep architecture and it's acting mechanism remains unclear. In the present study, we evaluated the sedative-hypnotic effect of cannabidiol (CBD), assessed the effects of CBD on sleep using a wireless physiological telemetry system. We further explored the therapeutic effects of CBD using 4-chloro-dl-phenylalanine (PCPA) induced insomnia model and changes in sleep latency, sleep duration and intestinal flora were evaluated. CBD shortened sleep latency and increases sleep duration in both normal and insomnia mice, and those effects were blocked by 5-HT1A receptor antagonist WAY100635. We determined that CBD increases 5-HT1A receptors expression and 5-HT content in the hypothalamus of PCPA-pretreated mice and affects tryptophan metabolism in the intestinal flora. These results showed that activation of 5-HT1A receptors is one of the potential mechanisms underlying the sedative-hypnotic effect of CBD. This study validated the effects of CBD on sleep and evaluated its potential therapeutic effects on insomnia.

An integrated liver, hippocampus and serum metabolomics based on UPLC-Q-TOF-MS revealed the therapeutical mechanism of Ziziphi Spinosae Semen in p-chlorophenylalanine-induced insomnia rats.

Ziziphi Spinosae Semen (ZSS), a well-known herbal medicine for treating insomnia, is popular in not only China but also in Europe, India and Iran. However, its underlying mechanisms remain unclear. In this work, taking the targeted organs of insomnia, the liver and hippocampus, as the objects, a combination metabolomics based on ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was established to illustrate the abnormality of metabolic characteristics of the liver, hippocampus and serum of p-chlorophenylalanine (PCPA)-induced insomnia rats and to demonstrate the mechanism of ZSS in treating insomnia. The results showed that ZSS could restore the brain cell morphology, decrease the degree of hepatocyte necrosis and regulate the disturbance of neurotransmitters and hormones in insomnia rats. In terms of metabolomics, a total of 33 liver metabolites, 25 hippocampal metabolites and 18 serum metabolites were finally selected as the potential biomarkers and an important pathway of phenylalanine, tyrosine and tryptophan biosynthesis was common in three tissues in PCPA rats. Meanwhile, ZSS significantly reversed the levels of 23 liver metabolites, 15 hippocampal metabolites and 5 serum metabolites. The present study demonstrates the actions of ZSS in treating insomnia by enhancing both cerebral and hepatic functions.

Effects of Antidepressants on Sleep in Post-traumatic Stress Disorder: An Overview of Reviews.

Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed.

Anti-insomnia Effect of a Polyherbal Formulation on P-chlorophenyalanine Induced Experimental Animal Model.

Sleep is a dynamic and controlled set of physiological and behavioural practices during which the stabilisation and restoration processes of the body take place properly. Therefore, sleep disorders, especially chronic insomnia, can harm an individual's physical and mental health. However, the therapeutic alternatives are limited and possess severe side effects. Thus, in this study, we aimed to investigate the anti-insomnia effect of a polyherbal formulation (Sleep) (SLP) on p-chlorophenyalanine (PCPA) induced insomnia in rats. Intraperitoneal injection of PCPA induced the experimental condition, and the therapeutic effect of SLP was evaluated by studying the sleep pattern and expression of various neurotransmitters and receptors, along with neurotrophins. Moreover, insomnia-associated oxidative stress and inflammation were also studied. From the findings, we found that the SLP-supplemented animals improved their sleeping behaviour and that the major neurotransmitters, hormones, and receptors were maintained at an equilibrium level. Furthermore, the neurotrophin level was increased and pro-inflammatory cytokines were reduced. The evaluation of oxidative stress markers shows that the antioxidants were significantly boosted, and as a result, lipid peroxidation was prevented. The overall findings suggest that SLP can be used as an effective medication for the treatment of sleep disorders like insomnia as it triggers the major neurotransmitter system.

The association between tacrolimus exposure and tremor, headache and insomnia in adult kidney transplant recipients: A systematic review.

PURPOSE: Tremor, headache and insomnia have been linked to the immunosuppressant, tacrolimus. The aim of this systematic review was to determine if there is a correlation between tacrolimus exposure and new-onset tremor, headache and insomnia experienced by adult kidney transplant recipients. METHODS: PubMed, Embase, Cochrane Library and CINAHL databases were searched up to 11 April 2023 for published studies which reported on tacrolimus exposure in adult kidney transplant recipients, alongside information on treatment-emergent neurologic manifestations, including tremor, headache and insomnia. Review articles, case studies, conference abstracts and articles not published in English in peer-reviewed journals were excluded. The Physiotherapy Evidence Database and Newcastle-Ottawa Quality Assessment Scales were used to assess risk of bias. Extracted data was analysed via a narrative synthesis. RESULTS: Eighteen studies involving 4030 patients in total were included in the final analysis. These comprised five randomised control trials and thirteen observational studies. Studies failed to find significant association between tacrolimus trough concentrations in whole blood and the incidence of neurologic side effects such as tremor, headache and insomnia; however, in one study the incidence of toxicity requiring a dose reduction increased with increasing, supratherapeutic targeted levels. Females, especially Black females, and older age were positively associated with the prevalence of neurologic adverse effects. Results were conflicting regarding whether extended-release formulations were associated with fewer neurologic complications than immediate-release formulations. CONCLUSION: The varied study designs and criteria for reporting tremor, headache and insomnia impacted on the quality of the data for exploring the relationship between tacrolimus exposure and the onset of neurologic manifestations experienced after kidney transplantation. Studies that examine defined neurologic complications as the primary outcome, and that consider novel markers of tacrolimus exposure while assessing the potential contribution of multiple covariate factors, are required.

Effects of aqueous extracts and volatile oils prepared from Huaxiang Anshen decoction on p-chlorophenylalanine-induced insomnia mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Insomnia occurs frequently in modern society, and its common symptoms include difficulty in falling asleep and decreased sleep quality and time, memory, and attention. With the advantages of having few side-effects and reduced drug-dependence, a compound traditional Chinese medicine (TCM) prescription called Huaxiang Anshen Decoction (HAD) has been widely used in clinical practice in China mainly for primary insomnia treatment. Although the effects of volatile oils from TCM herbs have been increasingly reported, volatile oils in HAD are conventionally neglected because of its preparation process and clinical usage. Therefore, exploring the anti-insomnia effects of volatile oils from HAD is of great importance. AIM OF THE STUDY: The sedative and hypnotic effects of the conventional aqueous extracts, the volatile oils from HAD, and their combinations were investigated. METHODS: The main components in HAD volatile oils (HAD-Oils), were analyzed through gas chromatography-mass spectrometry (GC-MS). The HAD volatile oil inclusion complex (HAD-OIC) was prepared with ß-cyclodextrin, and characterized. P-chlorophenylalanine (PCPA) was used to induce insomnia mice model and the test groups of HAD aqueous extract (HAD-AE), HAD-OIC and their combination (AE-OIC). An open field test was used in evaluating the mice's activities, and the levels of 5-hydroxytryptamine (5-HT) in mice sera, glutamate (Glu) in the hypothalamus, and γ-aminobutyric acid (γ-GABA) and dopamine (DA) in the brain tissues were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: A total 74 components in HAD-Oil were determined by GC/MS, and cyperenone (20.46%) and α-cyperone (10.39%) had the highest relative content. The characterization results of the physical phase showed that volatile oils were successfully encapsulated by ß-cyclodextrin and HAD-OIC was produced. The average encapsulation rates of cyperenone and α-cyperone were 79.93% and 71.96%, respectively. The results of pharmacology study showed that all the test groups increased the body weight and decreased voluntary activity when compared with the model group (P < 0.05). The HAD-AE, HAD-OIC, and AE-OIC groups increased the levels of 5-HT in the sera and DA and Glu/γ-GABA in the brains, and AE-OIC groups showed better performance than the other test groups. CONCLUSIONS: HAD-Oil exerts sedative and hypnotic effects, which are increased when it is used with HAD-AEs. This result provides a favorable experimental evidence that volatile oils should be retained for the further development of HAD.

[Research progress in pharmacotherapy of insomnia].

Insomnia is extremely common and is a risk factor for a variety of physical and psychological disorders in addition to contributing to the reduced quality of life of patients and the burden of healthcare costs. Although cognitive behavioral therapy is the first-line treatment for insomnia, its difficulty of access and high cost have hindered its application. Therefore, pharmacotherapy remains the common treatment choice for patients and clinicians. Existing chemical drugs including benzodiazepine receptor agonists, dual orexin receptor antagonists, melatonin and its receptor agonists, histamine antagonists, antidepressants, and antipsychotics are able to induce and/or maintain sleep and have good therapeutic effects on acute insomnia, but their efficacy on chronic insomnia is indefinite. Furthermore, they have several side effects and affect sleep structure and physiological function. Under the guiding principle of holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has shown a good effect in clinical practice, but with little high-grade clinical evidence. The mechanism, dose, half-life period, adjustment of sleep structure, and side effects of hypnotic drugs are key factors to be considered for clinical use. This paper analyzed and summarized the drugs for insomnia from the above aspects, and is expected to provide references for the application and development of sedative and hypnotic drugs.

Sleep Quality After Quetiapine Augmentation in Patients With Treatment-Resistant Depression and Personality Disorders.

PURPOSE/BACKGROUND: Quetiapine is a first-line augmenting agent for treatment-resistant depression (TRD) and is used off-label in insomnia. Quetiapine and its active metabolite norquetiapine act mostly on 5-HT2A, 5-HT2C, H1, and D2 as antagonists and on 5-HT1A as partial agonists. Patients with TRD often have comorbid personality disorder (PD), and evidence suggests an association between sleep disturbance and recovery among patients with PD. Here, we aimed to evaluate the effects of quetiapine on sleep in TRD patients with and without PD (PD+/PD-). METHODS/PROCEDURES: We reviewed health records of 38 patients with TRD (20 TRD/PD+) who had been treated with a pharmacotherapy regimen including quetiapine. Clinical outcomes were determined by comparing changes in sleep items of the Hamilton Depression Rating Scale at the beginning (T0) and after 3 months of an unchanged treatment (T3). FINDINGS/RESULTS: Patients with TRD/PD+ and TRD/PD- taking quetiapine showed significant improvement in sleep items from T0 to T3 (P < 0.001, ηp2 ≥ 0.19). There was a significant personality × time interaction for sleep-maintenance insomnia (P = 0.006, ηp2 = 0.23), with TRD/PD+ showing a greater improvement at T3 compared with TRD/PD- (P = 0.01). While exploring other sleep items, no personality × time interaction was found. In the TRD/PD- group, improvement in sleep items was associated with an overall improvement in depressive symptoms (r = 0.55, P = 0.02). IMPLICATIONS/CONCLUSIONS: Quetiapine induced greater improvements in sleep-maintenance insomnia among TRD/PD+ patients than TRD/PD-. These findings suggest quetiapine could have a therapeutic role for insomnia in PD underscoring a distinct underlying neurobiological mechanism of sleep disturbance in people living with PD.

[Factors associated with benzodiazepines dependence in insomnia patients]. / Factores asociados a la dependencia a benzodiacepinas en pacientes con insomnio.

Background: The use of benzodiazepines as a treatment for insomnia can have side effects such as impaired coordination causing falls in adults and even dependence. Objective: To assess the factors associated with dependence on benzodiazepines in patients with insomnia. Methods: Observational, cross-sectional, prospective, and analytical study, at the first level of care. Patients older than 18 years with a diagnosis of insomnia and a benzodiazepine prescription were selected. The dependency was measured with the International Neuropsychiatric Interview. Results: 107 patients were included. Median age 67 years, predominantly female (72%), 74% attended secondary school or more, 71% had more than 3 years of diagnosis, 84% used clonazepam. The 54% presented dependency. In the bivariate analysis, schooling RM 0.392 (95%CI: 0.15-0.96) p = 0.038, moderate and severe clinical insomnia RM 3.618 (95%CI: 1.44-9.08) p = 0.005 and more than 3 years of diagnosis RM 2.428 (95%CI: 1.03-5.71) p = 0.040. In the multivariate model, schooling (p = 0.084), years of diagnosis (p = 0.062) and frequency of consumption (p = 0.065) obtained an R2 of 0.13. Conclusions: Primary schooling showed a lower risk of presenting dependence on benzodiazepines. The risk was increased in those with more than 3 years of diagnosis, and in those with moderate and severe insomnia.

Introducción: el uso de benzodiacepinas como tratamiento para el insomnio puede tener efectos secundarios, como el deterioro de la coordinación que puede provocar caídas en adultos e, incluso, dependencia. Objetivo: evaluar los factores asociados a la dependencia a benzodiacepinas en pacientes con insomnio. Material y métodos: estudio observacional, transversal, prospectivo y analítico, llevado a cabo en el primer nivel de atención. Se seleccionaron pacientes mayores de 18 años con diagnóstico de insomnio y prescripción de benzodiacepina. La dependencia se midió con la Entrevista Neuropsiquiátrica Internacional. Resultados: se incluyeron 107 pacientes, la mediana de edad fue de 67 años, con predominio del sexo femenino (72%), el 74% cursó educación secundaria o más, el 71% tenía más de tres años con diagnóstico de insomnio, el 84% usaba clonazepan. El 54% presentó dependencia. En el análisis bivariado, la escolaridad primaria mostró una razón de momios (RM) de 0.392 (IC95%: 0.15-0.96), p = 0.038; el insomnio clínico moderado y grave RM de 3.618 (IC95%: 1.44-9.08) p = 0.005, y más de tres años de diagnóstico con una RM de 2.428 (IC95%: 1.03-5.71) p = 0.040. En el modelo multivariado, la escolaridad (p = 0.084), los años de diagnóstico (p = 0.062) y la frecuencia de consumo (p = 0.065) obtuvieron una R2 de 0.13. Conclusiones: los pacientes con escolaridad primaria mostraron un menor riesgo de presentar dependencia a benzodiacepinas. El riesgo se incrementó en los pacientes con más de tres años de diagnóstico y en aquellos con insomnio moderado y grave.

Exposure to secondhand smoke is associated with poor sleep quality among non-smoking university students in Bangladesh: a cross-sectional survey.

Although secondhand smoke (SHS) exposure is predominant in Bangladesh, the adverse effect of SHS exposure on health-related behaviors, such as sleep quality, have remained an under-investigated area of the country's public health landscape. Therefore, the purpose of this study was to examine the association between SHS exposure and poor sleep quality among non-smoking university students in Bangladesh. A cross-sectional survey was carried out between May and September 2022. SHS exposure (main predictor variable) and other covariates (e.g., age, sex, etc.) were measured using a self-reported questionnaire and sleep quality (outcome variable) was measured via the Pittsburgh Sleep Quality Index. Multiple logistic regression models investigated the association between SHS exposure and poor sleep quality. The study included 390 students (mean age: 22 years, 53.8% male). Approximately 41.8% of the participants reported SHS exposure, and 50.5% had poor sleep quality. Students exposed to SHS were more likely to have poor sleep quality compared to their counterparts (AOR = 1.61; 95% CI 1.01, 2.58). Subgroup analysis revealed poor sleep quality was 2-times higher among male students exposed to SHS than those male students without SHS exposure (AOR = 2.03; 95% CI 1.05, 3.93). No association was found in female students. Findings from this study warrant increased awareness and public health initiatives on the implications of SHS on health behaviors, such as sleep quality, in non-smoking Bangladeshi university students.

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

Efficacy of melatonin and ramelteon for the acute and long-term management of insomnia disorder in adults: A systematic review and meta-analysis.

Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta-analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = -6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = -5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = -8.74 min), and oSOL (p = 0.017; weighted difference = -14 min). Regarding long-term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes.

Therapeutic dilemma's: antipsychotics use for neuropsychiatric symptoms of dementia, delirium and insomnia and risk of falling in older adults, a clinical review.

PURPOSE: Because of the common and increasing use of antipsychotics in older adults, we aim to summarize the current knowledge on the causes of antipsychotic-related risk of falls in older adults. We also aim to provide information on the use of antipsychotics in dementia, delirium and insomnia, their adverse effects and an overview of the pharmacokinetic and pharmacodynamic mechanisms associated with antipsychotic use and falls. Finally, we aim to provide information to clinicians for weighing the benefits and harms of (de)prescribing. METHODS: A literature search was executed in CINAHL, PubMed and Scopus in March 2022 to identify studies focusing on fall-related adverse effects of the antipsychotic use in older adults. We focused on the antipsychotic use for neuropsychiatric symptoms of dementia, insomnia, and delirium. RESULTS: Antipsychotics increase the risk of falls through anticholinergic, orthostatic and extrapyramidal effects, sedation, and adverse effects on cardio- and cerebrovascular system. Practical resources and algorithms are available that guide and assist clinicians in deprescribing antipsychotics without current indication. CONCLUSIONS: Deprescribing of antipsychotics should be considered and encouraged in older people at risk of falling, especially when prescribed for neuropsychiatric symptoms of dementia, delirium or insomnia. If antipsychotics are still needed, we recommend that the benefits and harms of antipsychotic use should be reassessed within two to four weeks of prescription. If the use of antipsychotic causes more harm than benefit, the deprescribing process should be started.

Extended-Release Viloxazine Compared with Atomoxetine for Attention Deficit Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due to the potential for appetite and growth suppression, insomnia, wear off, exacerbation of mood, anxiety, and tics, or misuse. We utilize extended-release (ER) alpha-2 agonists primarily for hyperactivity/impulsivity but find them less effective for inattention, and they can cause sedation and hypotension. Oftentimes, we need to combine an alpha-2 agonist for behavior with psychostimulants for inattention. We employ atomoxetine or viloxazine ER (VER) for combined ADHD. However, our patients' insurers mandate a trial of generic atomoxetine prior to covering branded VER. The objective of this study was to determine whether pediatric and adult patients taking atomoxetine for DSM-5-TR ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to VER. METHODS: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after a 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to US Food and Drug Administration (FDA) guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine, and 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; the same protocol was used after treatment with VER. We conducted a blinded, de-identified, retrospective review of charts from these 50 patients in the regular course of outpatient practice. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05. RESULTS: From the baseline total ADHD-RS-5 mean score (40.3 ± 10.3), improvements were greater on VER (13.9 ± 10.2) than atomoxetine (33.1 ± 12.1; t = - 10.12, p < 0.00001) in inattention (t = - 8.57, p < 0.00001) and in hyperactivity/impulsivity (t = - 9.87, p < 0.00001). From the baseline total AISRS mean score (37.3 ± 11.8), improvements were greater on VER (11.9 ± 9.4) than atomoxetine (28.8 ± 14.9; t = - 4.18, p = 0.0009) in inattention (t = - 3.50, p < 0.004) and in hyperactivity/impulsivity (t = - 3.90, p < 0.002). Of patients on VER, 86% reported positive response by 2 weeks versus 14% on atomoxetine. A total of 36% discontinued atomoxetine for side effects, including gastrointestinal (GI) upset (6 patients), irritability (6), fatigue (5), and insomnia (1), versus 4% who discontinued VER due to fatigue. A total of 96% preferred VER over atomoxetine, with 85% (22 out of 26) choosing to taper psychostimulants following stabilization on VER. CONCLUSIONS: Pediatric and adult ADHD patients who have experienced less than optimal response to atomoxetine demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on extended-release viloxazine.

[Comparative study of the clinical efficacy and safety of the fixed dose combination Levroso Long with Melaxen and Diphenhydramine in patients with insomnia]. / Rezul'taty sravnitel'nogo klinicheskogo issledovaniya effektivnosti i bezopasnosti kombinirovannogo lekarstvennogo preparata Levroso Long s preparatami Melaksen i Dimedrol u patsientov s bessonnitsei.

OBJECTIVE: Evaluation of the efficacy and safety of Levroso Long (fixed dose combination (hereinafter referred to as «FDC¼) diphenhydramine and melatonin, 25 mg + 3 mg and FDC diphenhydramine and melatonin 50 mg + 3 mg, respectively, capsules with modified release, NovaMedica Innotech LLC) in comparison with diphenhydramine medicines 50 mg (Diphenhydramine tablets, DALHIMFARM OJSC, Russia) and 3 mg melatonin (Melaxen tablets, Unipharm Inc., USA) in patients with insomnia. MATERIALS AND METHODS: Material and methods. A multicenter open randomized comparative clinical trial was conducted in parallel groups. The study included 312 patients with an insomnia diagnosis verified in accordance with the DSM-IV criteria (ICD code F51.0-10) and an insomnia severity index (ICI) >8 points. The patients were randomized into 4 groups and took the following medications for 10 days: patients of group 1 - Levroso Long (25 mg diphenhydramine and 3 mg melatonin), group 2 - Levroso Long combination drug (50 mg diphenhydramine and 3 mg melatonin), Group 3 -Diphenhydramine 50 mg, 4th - Melaxen 3 mg. A comparative assessment was performed on the 7th and 10th days of therapy according to the primary endpoint - ICI, and secondary endpoints - the results of the assessment based on the Leeds Sleep Assessment Questionnaire, the Pittsburgh Sleep Quality Questionnaire, the Scale of the overall clinical impression of improvement and the analysis of the profile of adverse events (NA). RESULTS: The FDC of diphenhydramine 25 mg + melatonin 3 mg was more effective than diphenhydramine 50 mg, and FDC diphenhydramine 50 mg + melatonin 3 mg was more effective than diphenhydramine 50 mg or melatonin 3 mg on both primary and secondary endpoints. In a safety assessment, the highest incidence of adverse events (48.7%) in the diphenhydramine 50 mg group was significantly lower in groups 1 (29.5%), 2 (12.8%) and 4 (1.3%). All reported adverse events in the FDC groups were mild or moderate in severity. CONCLUSION: The study showed that Levroso Long in two dosages surpassed monotherapy with 50 mg of Diphenhydramine (50 mg) or Melaxen (3 mg) in patients with insomnia in terms of efficacy parameters. The benefit/risk ratio of the studied drug is favorable compared to monotherapy.

Acupuncture for chemotherapy-associated insomnia in breast cancer patients: an assessor-participant blinded, randomized, sham-controlled trial.

BACKGROUND: Insomnia is a highly prevalent symptom occurred during and post-chemotherapy. Acupuncture may have beneficial effects in the management of chemotherapy-associated insomnia. This study was conducted to determine the efficacy and safety of acupuncture in improving chemotherapy-associated insomnia in breast cancer patients. METHODS: This assessor-participant blinded, randomized, sham-controlled trial was conducted from November 2019 to January 2022 (follow-up completed July 2022). Participants were referred by oncologists from two Hong Kong hospitals. Assessments and interventions were conducted at the outpatient clinic of School of Chinese Medicine, the University of Hong Kong. The 138 breast cancer patients with chemotherapy-associated insomnia were randomly assigned to receive either 15 sessions of active acupuncture regimen by combining needling into body acupoints and acupressure on auricular acupoints or sham acupuncture control (69 each) for 18 weeks, followed by 24 weeks of follow-up. The primary outcome was measured using Insomnia Severity Index (ISI). Secondary outcomes included the Pittsburgh Sleep Quality Index, Actiwatch and sleep diary for sleep parameters, depression and anxiety, fatigue and pain, and quality of life. RESULTS: There were 87.7% (121/138) participants who completed the primary endpoint (week-6). The active acupuncture regimen was not superior to the sham control in reducing ISI score from baseline to 6 weeks (mean difference: - 0.4, 95% CI - 1.8-1.1; P = 0.609), but produced short-term treatment and long-term follow-up better outcomes in improving sleep onset latency, total sleep time, sleep efficiency, anxiety, depression, and quality of life. Participants of the active acupuncture group had a pronouncedly higher cessation rate of sleeping medications than the sham control (56.5% vs. 14.3%, P = 0.011). All treatment-related adverse events were mild. No participants discontinued treatments due to adverse events. CONCLUSION: The active acupuncture regimen could be considered as an effective option for the management of chemotherapy-associated insomnia. It also could serve as a tapering approach to reduce and even replace the use of sleeping medications in breast cancer patients. Trial registration Clinicaltrials.gov : NCT04144309. Registered 30 October 2019.

Electroacupuncture of the cymba concha alleviates p-chlorophenylalanine-induced insomnia in mice.

OBJECTIVE: Insomnia is the most common sleep disorder and is often comorbid with mental and physical diseases. The present study was designed to investigate the hypnotic effect of electroacupuncture (EA) of the cymba concha to stimulate the auricular branch of the vagus nerve (ABVN). METHODS: Mice were intraperitoneally injected with p-chlorophenylalanine (PCPA, 300 mg/kg·d) for 2 days to induce insomnia and subsequently received EA or manual acupuncture (MA) of the cymba concha for 30 min once daily for 5 consecutive days, or no treatment. The phenobarbital-induced sleep test was used to analyze the hypnotic effects and the open field test was used to analyze the locomotor activities and anxiolytic effects of EA/MA of the cymba concha. In addition, the levels of gamma-aminobutyric acid (GABA) and glutamate (Glu) in the hypothalamus and peripheral blood were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: PCPA injection significantly decreased sleep duration, increased sleep latency and induced anxiety-like behaviors in mice. In PCPA-insulted mice, EA of the cymba concha improved the sleep disturbance by significantly prolonging sleep duration, while no change in sleep latency was observed. Moreover, EA of the cymba concha improved PCPA-induced anxiety-like behaviors without decreasing locomotor activities in the open field test. EA of the cymba concha increased the level of GABA in the hypothalamus and peripheral blood, while Glu concentrations remained unchanged. CONCLUSION: These findings indicate that EA of the region innervated by the ABVN upregulates GABA levels in the hypothalamus and ameliorates the symptoms of insomnia and anxiety, suggesting that EA of the cymba concha might have potential value as an intervention for insomnia.