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Lancet (London, England) Oct 2021Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia.
METHODS
This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897.
FINDINGS
Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065).
INTERPRETATION
This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.
FUNDING
UK National Institute for Health Research Health Technology Assessment Programme.
Topics: Aged, 80 and over; Anti-Anxiety Agents; Brief Psychiatric Rating Scale; Caregivers; Dementia; Double-Blind Method; Female; Humans; Male; Mirtazapine; Psychomotor Agitation; Quality of Life; United Kingdom
PubMed: 34688369
DOI: 10.1016/S0140-6736(21)01210-1 -
Molecules (Basel, Switzerland) Apr 2022Aromas have a powerful influence in our everyday life and are known to exhibit an array of pharmacological properties, including anxiolytic, anti-stress, relaxing, and... (Review)
Review
Aromas have a powerful influence in our everyday life and are known to exhibit an array of pharmacological properties, including anxiolytic, anti-stress, relaxing, and sedative effects. Numerous animal and human studies support the use of aromas and their constituents to reduce anxiety-related symptoms and/or behaviours. Although the exact mechanism of how these aromas exert their anxiolytic effects is not fully understood, the GABAergic system is thought to be primarily involved. The fragrance emitted from a number of plant essential oils has shown promise in recent studies in modulating GABAergic neurotransmission, with GABA receptors being the primary therapeutic target. This review will explore the anxiolytic and sedative properties of aromas found in common beverages, such as coffee, tea, and whisky as well aromas found in food, spices, volatile organic compounds, and popular botanicals and their constituents. In doing so, this review will focus on these aromas and their influence on the GABAergic system and provide greater insight into viable anxiety treatment options.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Hypnotics and Sedatives; Odorants; Oils, Volatile; Plant Oils; Receptors, GABA-A
PubMed: 35458615
DOI: 10.3390/molecules27082414 -
Journal of Alternative and... Sep 2020This exploratory analysis examined the putative antidepressant effect of L. (chamomile) extract in subjects with generalized anxiety disorder (GAD) with or without... (Randomized Controlled Trial)
Randomized Controlled Trial
This exploratory analysis examined the putative antidepressant effect of L. (chamomile) extract in subjects with generalized anxiety disorder (GAD) with or without comorbid depression. It was hypothesized that chamomile extract would demonstrate similar anxiolytic activity in both subgroups, but superior antidepressant activity in GAD subjects with comorbid depression. As part of a randomized double-blind placebo-controlled trial of chamomile extract for relapse prevention of GAD, 179 subjects received initial therapy with open-label chamomile extract 1500 mg daily for 8 weeks. Linear mixed-effect models were used to identify clinically meaningful changes in anxiety and depression symptoms between diagnostic subgroups. The study took place at the University of Pennsylvania in Philadelphia, PA. Subjects were ≥18 years old with a primary DSM IV-TR diagnosis of GAD. They were subcategorized into two diagnostic groups: GAD without comorbid depression ( = 100) and GAD with comorbid depression ( = 79). Open-label chamomile extract 1500 mg was given daily for 8 weeks. Generalized anxiety disorder (GAD-7), Hamilton rating scale for anxiety, Beck anxiety inventory, Hamilton rating scale for depression (HRSD), the six-item core HRSD (items 1, 2, 3, 7, 8, and 13), and the Beck depression inventory (BDI). The authors observed similar anxiolytic effects over time in both diagnostic subgroups. However, there was a greater reduction in HRSD core symptom scores ( < 0.023), and a trend level reduction in HRSD total scores ( = 0.14) and in BPI total scores ( = 0.060) in subjects with comorbid depression. L. may produce clinically meaningful antidepressant effects in addition to its anxiolytic activity in subjects with GAD and comorbid depression. Future controlled trials in subjects with primary major depressive disorder are needed to validate this preliminary observation.
Topics: Administration, Oral; Adult; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Chamomile; Depression; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Male; Matricaria; Middle Aged; Phytotherapy; Plant Extracts; Psychiatric Status Rating Scales; Treatment Outcome
PubMed: 31808709
DOI: 10.1089/acm.2019.0252 -
Translational Psychiatry Jul 2020The aim of this review is to summarize evidence regarding rat emotional experiences during carbon dioxide (CO) exposure. The studies reviewed show that CO exposure is... (Review)
Review
The aim of this review is to summarize evidence regarding rat emotional experiences during carbon dioxide (CO) exposure. The studies reviewed show that CO exposure is aversive to rats, and that rats respond to CO exposure with active and passive defense behaviors. Plasma corticosterone and bradycardia increased in rats exposed to CO. As with anxiogenic drugs, responses to CO are counteracted by the administration of anxiolytics, SRIs, and SSRI's. Human studies reviewed indicate that, when inhaling CO, humans experience feelings of anxiety fear and panic, and that administration of benzodiazepines, serotonin precursors, and SSRIs ameliorate these feelings. In vivo and in vitro rat studies reviewed show that brain regions, ion channels, and neurotransmitters involved in negative emotional responses are activated by hypercapnia and acidosis associated with CO exposure. On the basis of the behavioral, physiological, and neurobiological evidence reviewed, we conclude that CO elicits negative emotions in rats.
Topics: Animals; Anti-Anxiety Agents; Brain; Carbon Dioxide; Emotions; Panic; Rats
PubMed: 32709846
DOI: 10.1038/s41398-020-00936-w -
Scientific Reports Dec 2019A systematic review and network-meta analysis (NMA) were performed to estimate significance of the anxiolytic effect of lavender essential oil taken as silexan capsules... (Comparative Study)
Comparative Study
A systematic review and network-meta analysis (NMA) were performed to estimate significance of the anxiolytic effect of lavender essential oil taken as silexan capsules versus other comparators (i.e., placebo/paroxetine/lorazepam). The outcome of interest was Hamilton Anxiety Scale (HAMA). Weighted mean differences (WMD) were calculated to estimate the treatment effect at the confidence interval of 95%. League tables were generated using treatment effect, for all pairwise comparisons, where WMD < 0 favors the column-defining treatment. Five studies were identified with a total of 524 participants receiving treatment with silexan 80 mg and 121 participants taking silexan 160 mg. The NMA results indicated that consumption of silexan 160 mg resulted in higher decline of HAMA score [WMD -1.14 (-1.10, 3.39)] in comparison to silexan 80 mg, placebo [-2.20 (-4.64, 0.24)] and paroxetine [-1.24 (-5.34, 2.85)]. The effect of silexan 80 mg was observed to be same as that of paroxetine. Overall, silexan 160 mg was noticed to be a more efficient treatment giving significant decline in HAMA score across other comparators. However, no improvements in HAMA score was observed for the group receiving lorazepam 0.5 mg when compared to silexan 160 mg, silexan 80 mg, paroxetine 20 mg, and placebo.
Topics: Anti-Anxiety Agents; Anxiety Disorders; Capsules; Humans; Lavandula; Lorazepam; Network Meta-Analysis; Oils, Volatile; Paroxetine; Personality Assessment; Plant Oils; Treatment Outcome
PubMed: 31792285
DOI: 10.1038/s41598-019-54529-9 -
Biomedicine & Pharmacotherapy =... Dec 2023Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular...
Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular mechanisms regulating emotional disorders remain unelucidated. Here we report unknown roles of protein palmitoylation/nitrosylation crosstalk in regulating anxiety-like behaviors in rats. According to the percentages of open arm duration in the elevated plus maze test, the rats were divided into high-, intermediate- and low-anxiety groups. The palmitoylation and nitrosylation levels were detected by acyl-biotin exchange assay, and we found low palmitoylation and high nitrosylation levels in the basolateral amygdala (BLA) of high-anxiety rats. Furthermore, we observed that 2-bromopalmitate (2-BP), a palmitoylation inhibitor, induced anxiety-like behaviors, accompanied with decreased amplitude and frequency of mEPSCs and mIPSCs in the BLA. Additionally, we also found that inhibiting nNOS activity with 7-nitroindazole (7-NI) in the BLA caused anxiolytic effects and reduced the synaptic transmission. Interestingly, diazepam (DZP) rapidly elevated the protein palmitoylation level and attenuated the protein nitrosylation level in the BLA. Specifically, similar to DZP, the voluntary wheel running exerted DZP-like anxiolytic action, and induced high palmitoylation and low nitrosylation levels in the BLA. Lastly, blocking the protein palmitoylation with 2-BP induced an increase in protein nitrosylation level, and attenuating the nNOS activity by 7-NI elevated the protein palmitoylation level. Collectively, these results show a critical role of protein palmitoylation/nitrosylation crosstalk in orchestrating anxiety behavior in rats, and it may serve as a potential target for anxiolytic intervention.
Topics: Rats; Animals; Basolateral Nuclear Complex; Anti-Anxiety Agents; Lipoylation; Motor Activity; Anxiety; Diazepam
PubMed: 37948993
DOI: 10.1016/j.biopha.2023.115859 -
Acta Gastro-enterologica Belgica 2023Functional dyspepsia is a common chronic condition with upper abdominal symptoms in the absence of an organic cause. The first line treatment consists of protonpomp... (Review)
Review
BACKGROUND AND STUDY AIMS
Functional dyspepsia is a common chronic condition with upper abdominal symptoms in the absence of an organic cause. The first line treatment consists of protonpomp inhibition or Helicobacter pylori eradication. However, this approach often does not provide enough symptom relief. Neuromodulating agents are commonly used in clinical practice but only tricyclic antidepressant (TCAs) are mentioned in European and American and Canadian guidelines.
METHODS
We performed a comprehensive review of the literature in Pubmed for full-text randomized controlled trials in English with adult participants (>18 years) who met the Rome II, III or IV criteria or were diagnosed by a physician with a negative upper endoscopy and that compared a neuromodulating agent with placebo.
RESULTS
The search strategy identified 386 articles of which 14 articles met the eligibility criteria. TCAs like amitriptyline and imipramine have been shown to be effective in the treatment of functional dyspepsia whereas other neuromodulating agents like tetracyclic antidepressants, levosulpiride and anxiolytics might be beneficial but conclusive evidence is lacking. serotonin and noradrenaline reuptake inhibitors (SNRI) and selective serotonin reuptake inhibitors (SSRI) have not shown benefit in patients with functional dyspepsia.
CONCLUSION
Selected neuromodulators have an established efficacy in functional dyspepsia. The best supporting evidence is available for TCAs with a potential role for tetracyclic antidepressants, levosulpiride and anxiolytics.
Topics: Adult; Humans; Anti-Anxiety Agents; Antidepressive Agents; Antidepressive Agents, Tricyclic; Canada; Dyspepsia; Selective Serotonin Reuptake Inhibitors; Randomized Controlled Trials as Topic
PubMed: 36842175
DOI: 10.51821/86.1.10998 -
European Archives of Psychiatry and... Oct 2023We report on a meta-analysis of Silexan, a proprietary active substance produced from Lavandula angustifolia, in subthreshold anxiety, mixed anxiety and depressive... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
We report on a meta-analysis of Silexan, a proprietary active substance produced from Lavandula angustifolia, in subthreshold anxiety, mixed anxiety and depressive disorder (MADD), and generalized anxiety disorder (GAD).
METHODS
The present analyses are based on all currently completed 5 double-blind, randomized, placebo-controlled trials investigating Silexan in adult out-patients who received Silexan 1 × 80 mg/day or placebo for ten weeks according to random assignment (n = 1213). Efficacy was assessed based on the Hamilton Anxiety Rating Scale (HAMA), several anxiety self-rating scales, the Clinical Global Impression (CGI) scale, and the Short Form-36 (SF-36) health status questionnaire.
RESULTS
After ten weeks' treatment, Silexan was significantly superior to placebo in reducing the HAMA total score (including the psychic and somatic anxiety sub-scores) and self-rated anxiety. Based on a ≥ 50% HAMA total score reduction, the responder rate ratio was 1.34 favoring Silexan, and the rate ratio of subjects much or very much improved according to the CGI was 1.51. Silexan was also significantly superior in improving the physical and mental health summary scores of the SF-36. There were no significant between-group differences concerning the occurrence of adverse events (AEs), serious AEs, and premature withdrawal due to AEs.
CONCLUSIONS
This meta-analysis demonstrates that Silexan exerts significant anxiolytic effects in subthreshold anxiety, GAD and MADD that were consistently reflected in investigator ratings and patient-reported outcomes, including improvement of health-related life-quality, while showing favorable tolerability and safety.
Topics: Adult; Humans; Plant Oils; Oils, Volatile; Anxiety Disorders; Lavandula; Anti-Anxiety Agents; Double-Blind Method; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 36717399
DOI: 10.1007/s00406-022-01547-w -
Physiology & Behavior Nov 2023Anxiety disorders pose a significant challenge in contemporary society, and their impact in terms of social and economic burden is overwhelming. Behavioral research... (Review)
Review
Anxiety disorders pose a significant challenge in contemporary society, and their impact in terms of social and economic burden is overwhelming. Behavioral research conducted on animal subjects is crucial for comprehending these disorders and, from a translational standpoint, for introducing innovative therapeutic approaches. In this context, the Hole-Board apparatus has emerged as a widely utilized test for studying anxiety-related behaviors in rodents. Although a substantial body of literature underscores the utility and reliability of the Hole-Board in anxiety research, recent decades have witnessed a range of studies that have led to uncertainties and misinterpretations regarding the validity of this behavioral assay. The objective of this review is twofold: firstly, to underscore the utility and reliability of the Hole-Board assay, and concurrently, to examine the underlying factors contributing to potential misconceptions surrounding its utilization in the study of anxiety and anxiety-related behaviors. We will present results from both conventional quantitative analyses and multivariate approaches, while referencing a comprehensive collection of studies conducted using the Hole-Board.
Topics: Humans; Animals; Reproducibility of Results; Behavior, Animal; Anxiety; Anti-Anxiety Agents; Anxiety Disorders; Exploratory Behavior
PubMed: 37690695
DOI: 10.1016/j.physbeh.2023.114346 -
Genes May 2023Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and... (Review)
Review
Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient's individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug's absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient's response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment.
Topics: Humans; Pharmacogenetics; Anti-Anxiety Agents; Cytochrome P-450 Enzyme System; ATP-Binding Cassette Transporters; Antidepressive Agents
PubMed: 37239455
DOI: 10.3390/genes14051095