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Microglia are resident brain cells that regulate neuronal development and innate immunity. Microglia activation participates in the cellular response to neuroinflammation, thus representing a possible target for pharmacological strategies aimed to counteract the onset and progression of brain disorders, including depression. Antidepressant drugs have been reported to reduce neuroinflammation by acting also on glial cells. Herein, the potential anti‐inflammatory and neuroprotective effects of trazodone (TRZ) on the microglial human microglial clone 3 (HMC3) cell line were investigated. HMC3 cells were activated by a double inflammatory stimulus (lipopolysaccharide [LPS] and tumour necrosis factor‐alpha [TNF‐α], 24 h each), and the induction of inflammation was demonstrated by (i) the increased expression levels of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐kB) and ionized calcium‐binding adapter molecule 1 (IBA‐1), and (ii) the increased release of interleukin 6 (IL‐6) and transforming growth factor‐beta (TGF‐β). TRZ effects were evaluated by treating HMC3 cells for 24 h before (pre‐treatment) and after (post‐treatment) the double inflammatory stimulus. Notably, TRZ treatments significantly decreased the expression of NF‐kB and IBA‐1 and the release of the cytokines IL‐6 and TGF‐β. Moreover, TRZ prevented and reduced the release of quinolinic acid (QUIN), a known neurotoxic kynurenine metabolite. Finally, cellular supernatants collected from microglial cells pre‐treated LPS‐TNF‐α with TRZ were able to improve neuronal‐like cell viability, demonstrating a potential neuroprotective effect. Overall, this study suggests the anti‐inflammatory effects of TRZ on human microglia and strives for its neuroprotective properties. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusions Antidepressants may lead to a series of sexual adverse effects (SAEs), among which ejaculation dysfunction (EjD) is often overlooked by clinicians. The purpose of the present network meta‐analysis was to assist drug adjustment by comparing and ranking the incidence of EjD among various antidepressants.Relevant studies were retrieved from PubMed, Embase, Scopus, Web of Science, ClinicalTrials.gov, and other additional records. Eligible randomized controlled trials (RCTs) assessed the rate of EjD in patients with major depressive disorder (MDD) and anxiety disorder after taking anti‐depressants. The incidences of EjD, erectile dysfunction (ED), decreased libido (DL), adverse events (AE), withdrawal due to adverse events (WDAE) and withdrawal due to lack of efficacy (WDLE) were pooled using odds ratio (OR) with their 95% confidence intervals (CI). The values of surface under the cumulative ranking curve (SUCRA) helped to rank the risk of each outcome in different antidepressants.Thirty RCTs comprising 18,157 patients were included. Results of all node‐splitting analysis demonstrated no statistical inconsistency (all P > 0.05). Clomipramine (OR 42.11, 95% CI [9.90, 179.08]), WS5570 (OR 28.99, 95% CI [1.48, 568.97]) and paroxetine (OR 18.63, 95% CI [9.33, 37.23]) had significant risk of EjD comparing to placebo. Additionally, duloxetine (OR 7.37, 95% CI [2.61, 20.78]), clomipramine (OR 5.29, 95% CI [1.72, 16.25]), paroxetine (OR 3.75, 95% CI [1.37, 10.26]) and escitalopram (OR 3.04, 95% CI [1.20, 7.71]) presented higher risk of ED comparing to placebo. Agomelatine, levomilnacipran, vortioxetine, trazodone, vilazodone, fluvoxamine and imipramine exhibited similar incidence of EjD with placebo (all P > 0.05). Besides, trazodone, vilazodone and vortioxetine had the top‐five SUCRA values in each of SAEs (EjD, ED and DL), and agomelatine might be alternative in EjD and DL. Considering about AE, WDAE and WDLE, vilazodone appeared to offer more satisfactory performance across all these aspects.For patients undergoing SAEs following the administration of antidepressants, trazodone, vortioxetine, vilazodone and agomelatine are alternative antidepressants. [ABSTRACT FROM AUTHOR]

Background: Health‐related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real‐world effects of trazodone once‐a‐day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD. Methods: This 8‐week prospective, observational, open‐label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient‐reported Quality‐of‐Life Enjoyment and Satisfaction Questionnaire Short Form (Q‐LES‐Q‐SF) from baseline to week 8. Secondary outcomes included change in Q‐LES‐Q‐SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF‐SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith–Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ‐5) at baseline and week 8. Results: The study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q‐LES‐Q‐SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, −15.7 [8.3]; TzOAD, −21.0 [9.8]); PROMIS SF‐SD 8b (SSRI, −9.9 [12.6]; TzOAD, −22.0 [12.6]). Mean change scores in Q‐LES‐Q‐SF, MADRS, and PROMIS SF‐SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, −9.2 [7.4]; TzOAD, −14.3 [7.5]), SHAPS (SSRI, −6.6 [4.3]; TzOAD, −8.3 [4.4]), and PDQ‐5 (SSRI, −5.8 [4.5]; TzOAD, −7.7 [5.0]). Conclusions: In adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group. [ABSTRACT FROM AUTHOR]

The study's objective is to establish an eco‐friendly, sensitive and economical quantitative methodology for the concurrent analysis of donepezil HCl (DPZ) and trazodone HCl (TRZ) in raw materials, tablets and human plasma. The first derivative synchronous fluorescence spectroscopic (FDSFS) technique was applied at constant wavelength difference (∆λ = 120) for assessment of DPZ and TRZ at each other's zero‐crossing point at 279 nm and 297 nm, respectively. The submitted technique was validated in accordance with ICH Q2 R1 guidelines and the linearity of the standard calibration curve was observed over the concentration range of 10–500 ng/ml for DPZ and 20–1,000 ng/ml for TRZ. The detection limits (LOD) were found to be 2.65 and 5.4 ng/ml, and the limits of quantitation (LOQ) were 8.05 and 16.3 ng/ml for DPZ and TRZ, respectively. This technique was used further to quantify the studied medications in their laboratory‐prepared mixtures, commercial tablets and spiked plasma samples. The results obtained were not significantly different from those acquired from the comparison methods, indicating the high accuracy and precision of the proposed method. Furthermore, the ecological friendliness of the suggested method was evaluated and proven to be excellent using Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE) evaluation tools. [ABSTRACT FROM AUTHOR]

Summary: Sleep disturbances in people living with HIV (PLHIV) are frequent but their management remains insufficient. In the absence of specific recommendations, a DELPHI consensus research project was conducted in France to establish best practice. A multidisciplinary Steering Committee (STC) undertook a literature review and used it with clinical expertise to create statements that were voted on. Two profiles of healthcare professionals with significant experience in monitoring PLHIV were selected for the voting: physicians and nurses/psychologists. Votes were collected electronically, independently, and anonymously. The STC created 27 statements covering six areas: Screening of sleep disturbances, Investigation, First‐line management, Referral to a specialist, Antiretroviral treatment (ARV), and Prevention. Two rounds of votes included 42 physicians and 32 nurses/psychologists. Consensus was reached for 24 out of 27 statements (89%) including: to assess quantity and quality of sleep among PLHIV at least annually, ideally using a common methodology within the medical department; to consider the temporary addition of a hypnotic treatment in cases of acute insomnia not improved by the rules of sleep hygiene, with full awareness of potential drug–drug interactions and risk of dependence; to correct ferritinaemia if <100 ng/mL before referral to a specialist when restless legs syndrome is suspected; to consider changing the time of ARV administration or an ARV switch within the same class when sleep disturbances are caused by an ARV. This DELPHI Consensus provides best practice for screening and managing sleep disturbances in PLHIV and optimising their quality of life. [ABSTRACT FROM AUTHOR]

Background: Drug interactions are significant considerations for intradermal testing (IDT). Trazodone (TRZ) is an anxiolytic and selective histaminergic (H1) antagonist with no interaction in human prick tests; however, interaction in canine IDT is unknown. Hypothesis/Objectives: Trazodone will not adversely affect intradermal histamine reactions in dogs. Animals: Fourteen nonanxious, nonatopic, healthy client‐owned dogs were enrolled in this randomised, blinded, cross‐over study. Materials and Methods: Dogs were randomised to receive low‐dose TRZ (4 mg/kg) (Teva Pharmaceuticals), high‐dose TRZ (8 mg/kg) or no TRZ per os two hours before intravenous sedation with dexmedetomidine (5 mcg/kg) (Dexdomitor; Zoetis). Intradermal testing was performed with five quadrupling dilutions of histamine (1:100,000 to 1:25,600,000 w/v; Greer) and 0.9% saline (Hospira), observing a minimum two weeks washout period between treatments. Two observers, who were blinded to treatment and the identity of the injections, evaluated each test using previously established subjective and objective methods. Results: The mean wheal diameter of histamine 1:1,600,000 w/v was significantly smaller with low‐dose TRZ (4 mg/kg) compared to the control group (p = 0.048; repeated measures ANOVA with post hoc Tukey's test). For all other histamine dilutions and saline, mean wheal diameter was not significantly different among groups. There were no significant differences in the subjective scores of all histamine dilutions and saline (p > 0.05; Friedman test). Conclusion and Clinical Relevance: A single oral dose of TRZ does not adversely affect intradermal histamine reactions in dogs. [ABSTRACT FROM AUTHOR]

Background: Conditions affecting the hypothalamic‐pituitary‐adrenal (HPA) axis are common in dogs. Testing the function of the HPA axis includes measurement of endogenous adrenocorticotropic hormone (eACTH) and performance of an adrenocorticotropic hormone (ACTH) stimulation test. Trazodone is commonly administered to dogs to decrease stress. In humans, trazodone significantly decreases plasma cortisol concentration via alpha‐1 adrenergic activity. Objectives: Determine the influence of trazodone on eACTH and serum cortisol concentrations in healthy dogs. Animals: Fourteen healthy, adult, companion dogs. Methods: Prospective, randomized placebo‐controlled study. Trazodone (8‐10 mg/kg) or placebo was administered PO 1 hour before eACTH measurement and ACTH stimulation testing. After a ≥7‐day wash‐out period, dogs received the opposite treatment. Differences in eACTH, pre‐ and post‐ACTH stimulation cortisol concentrations, and delta (difference between pre‐ and post‐ACTH) cortisol concentrations were analyzed using a paired t or signed‐rank test with a P <.05 significance level. Results: The eACTH concentrations were not significantly different (P =.23) between treatments. Similarly, no significant differences were found in the pre‐ACTH cortisol concentrations between treatments (P =.40). Post‐ACTH cortisol concentrations (P =.05) and delta cortisol concentrations (P =.04) were significantly lower when the dogs were treated with trazodone. Conclusions: Preliminary data suggest trazodone administration dampens the adrenocortical response to stimulation in healthy dogs. If similar effects are found in dogs with adrenal disease, the use of trazodone may affect diagnosis and clinical decision making in these populations. [ABSTRACT FROM AUTHOR]

Summary: This article reviews the history of insomnia pharmacotherapy, documenting the evolution that has occurred over time in the increasing availability of medications with novel mechanisms of action that more specifically target the neural systems that modulate sleep/wake function. This evolution provides an increasing capacity to improve the effectiveness of insomnia pharmacotherapy by allowing the selection of medications that specifically target the particular type of sleep difficulty present in each patient. As a result, they can achieve a therapeutic effect with fewer effects on aspects of brain function other than those needed to achieve benefit, thereby minimising adverse effects. The accumulated evidence‐base is such that it can serve as the basis for a personalised insomnia pharmacotherapy paradigm. Here we outline a set of best‐practice recommendations for how to carry out optimised personalised insomnia pharmacotherapy based on that evidence base in the hope that it will improve the treatment delivered to the many individuals suffering from insomnia. [ABSTRACT FROM AUTHOR]

Summary: Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential‐diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep‐related breathing disorders, etc.), treatment‐resistant insomnia (A) and for other indications (B). Cognitive‐behavioural therapy for insomnia is recommended as the first‐line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in‐person or digitally (A). When cognitive‐behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low‐dose sedating antidepressants (B) can be used for the short‐term treatment of insomnia (≤ 4 weeks). Longer‐term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged‐release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast‐release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive‐behavioural therapy for insomnia (B). [ABSTRACT FROM AUTHOR]

Background: Trazodone is a serotonin antagonist/reuptake inhibitor medication commonly used for anxiety in dogs. Therapy with selective serotonin reuptake inhibitors in humans is associated with bleeding disorders and increased arrhythmogenesis. Hypothesis/Objectives: To evaluate markers of primary hemostasis and corrected QT (cQT) interval in dogs before and after oral administration of standard dosages of trazodone or placebo. Animals: Fifteen apparently healthy, client‐owned dogs. Methods: A single‐blinded, randomized placebo‐controlled crossover study was performed. Dogs were administered trazodone (5 to 7.5 mg/kg PO Q12h) or placebo. [Correction added after first online publication on 14 October 2023. In the abstract (methods) section (57.5 mg/kg PO Q12h) changed as (5 to 7.5 mg/kg PO Q12h).] Buccal mucosal bleeding time (BMBT), platelet count, platelet aggregation via Plateletworks, PFA‐100 closure time and cQT interval were measured. A Shapiro‐Wilk test was performed followed by either a paired t test or a Wilcoxon signed‐rank test. Results: No significant difference was detected in the BMBT, PFA‐100 closure times, platelet counts, and cQT interval between trazodone or placebo. However, using Plateletworks, there was a significant decrease in platelet aggregation after administration of trazodone (95%; 81‐97 vs 62%; 39‐89, P =.002) and not placebo (95%; 81‐97 vs 91%; 81‐96, P =.21). Conclusions: It is unknown if this represents a clinically relevant change or if dogs with preexisting impairment in primary hemostasis or receiving higher dosages or longer durations of trazodone could have a more substantial change in hemostatic variables. [ABSTRACT FROM AUTHOR]

Background: Trazodone, a serotonin receptor antagonist and reuptake inhibitor, might be a useful adjunctive treatment in the initial management of horses with acute laminitis if it minimizes ambulation or encourages recumbency. Objectives: (1) Evaluate the effects of PO trazodone on ambulatory activity and recumbency in healthy horses; and (2) assess the pharmacokinetics of multiple PO doses of trazodone. Animals/Methods: In a randomized cross‐over design, 8 healthy horses received placebo or trazodone at 2 doses (2.5 and 7.5 mg/kg) PO q12h for 48 hours with a 14‐day washout period between treatments. Forelimb step frequency was measured using a hoof‐mounted accelerometer and continuous video monitoring was used to detect recumbency. Groups were compared using repeated measures analysis of variance with Tukey's post hoc test. Trazodone and m‐chlorophenylpiperazine (m‐CPP) plasma concentrations were determined by ultra‐high performance liquid chromatography‐tandem mass spectrometry and pharmacokinetics were analyzed using noncompartmental methods. Results: Step frequency was lower in horses receiving 7.5 mg/kg trazodone than in the control group (mean step reduction: 44% ± 11%). Steps‐area under the curve were significantly lower in the 7.5 mg/kg group (mean ± SD: 3375 ± 525 steps × hour) as compared to the 2.5 mg/kg group (mean ± SD: 5901 ± 2232; P =.02) and compared to control (mean ± SD: 6590 ± 1241; P =.001). No difference was found in the number of recumbent episodes (P =.92) or total duration of recumbency (P =.9). Trazodone and m‐CPP achieved steady‐state concentrations, with an accumulation ratio of 1.45 ± 0.2. Conclusions and Clinical Importance: Although it did not affect recumbency, trazodone at 7.5 mg/kg q12h decreased step frequency by approximately 44%. [ABSTRACT FROM AUTHOR]

Trazodone and gabapentin are common oral sedatives in cats, used alone or combined, but no pharmacokinetic studies exist for trazodone in this species. The objective of this study was to determine the pharmacokinetics of oral trazodone (T) alone, or in combination with gabapentin (G) in healthy cats. Cats (n = 6) were randomly allocated to receive T (3 mg/kg) intravenously (IV), T (5 mg/kg) orally (PO), or T (5 mg/kg) and G (10 mg/kg) PO with a 1‐week washout period between treatments. Heart rate, respiratory rate, indirect blood pressure, and level of sedation were assessed, and venous blood samples were collected serially over 24 h. Analysis of plasma trazodone concentration was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Oral T administration resulted in a bioavailability of 54.9(7–96)%, and 17.2(11–25)% when administered with G. Tmax 0.17 (0.17–0.5) and 0.17 (0.17–0.75) h; Cmax 1.67 ± 0.91 and 1.22 ± 0.54 μg/mL, AUC 5.23 (2.0–18.76) and 2.37 (1.17–7.80) h*μg/mL; T1/2 5.12 ± 2.56 and 4.71 ± 1.07 h; for T and TG, respectively. Sedation was significant when compared to baseline in all groups from 20 or 45 min to 8 h indicating some lag between peak plasma concentration and sedative effects. Physiological variables remained within normal limits. This study concludes that oral trazodone is rapidly absorbed in healthy cats. Addition of gabapentin did not result in more profound sedation, showing no clinical advantage of combining these drugs in this study population. [ABSTRACT FROM AUTHOR]

See related article by Wastila et al. in this issue. [ABSTRACT FROM AUTHOR]

A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the time course of writhings after intraperitoneal injection of acetic acid in mice. The model was applied to investigate the antinociceptive effect of trazodone and gabapentin alone and in combination. Writhings time course was described by a transit compartment model with the delay due to the transit of the acetic acid being represented by a chain of intermediate compartments. In the drug‐treated animals, the number of writhings decreases according to a k2 factor linking drug concentration and antinociceptive effect. Compounds' potency parameters were 10.9 and 0.0459 L/μmoles/min for trazodone and gabapentin, respectively, indicating a much higher in vivo potency of trazodone in the PD writhing test. The PK/PD parameters were used to simulate the expected writhing counts in mice at combined doses without efficacy alone, assuming pharmacological additivity. Simulation results indicated that, at low dose combinations, experimental data were mostly below the simulated writhings median, suggesting possible synergic effect. Such hypothesis was tested by adding the γ parameter in the PK/PD model to represent the deviation from the assumption of no‐interaction, leading to a reduction of the objective function compared to the additive model. On this basis, several simulations were performed to identify possible starting dose combinations of trazodone and gabapentin in humans, by selecting doses yielding systemic exposures close to those being synergic in the mouse. Simulations indicated that doses of 50–100 mg trazodone could enhance gabapentin antinociceptive effect in humans, supporting the development of a low dose combination for optimal analgesia treatment. [ABSTRACT FROM AUTHOR]

In this prospective follow‐up study, we aimed to examine whether changes in self‐reported sleep quality, sleep duration, and sleep medication use are temporally associated with changes in quality of life and work ability in municipal employees when several confounding factors are considered. The study was conducted in Finland among 637 municipal employees (88% women, mean [SD] age 48 [10] years) in 2014 and 2015. Information about the participants was collected by self‐administered questionnaire and from medical history. Predicting variables were changes in self‐reported sleep quality, sleep duration, and sleep medication use. Outcome variables were changes in the EUROHIS‐QOL eight‐item index and the Work Ability Score. Improved or unchanged sleep quality compared to worse sleep quality were associated with a preferable change in quality of life (both p < 0.001). No change in sleep duration compared to a decrease and no change in sleep medication use compared to increased use were also associated with favourable changes in quality of life. Increased use of sleep medication was associated with a decline in work ability, and the change in Work Ability Score also differed significantly between improved and worsened sleep quality. In this study, changes in sleep were widely associated with changes in quality of life and work ability of municipal employees. Programmes aiming for better sleep health would probably be beneficial both from a health‐oriented and an economical point of view. Special attention should be paid to employees with a need for sleep medication. [ABSTRACT FROM AUTHOR]

Aim: No consensus has been reached on the association between the risk of falls and antipsychotic and antidepressant drug use. In this study, we evaluated the risk of falls with trazodone, risperidone, and quetiapine, which are recommended for use at Kanazawa Medical University Hospital. Methods: We reviewed all patients who were admitted to Kanazawa Medical University Hospital between January 1st and December 31st, 2018. We excluded those aged <20 years and those admitted to pediatric, intensive care, and psychiatric wards. Finally, 9273 patients were included. We reviewed the incidence in these patients of accidental falls reported to the medical safety department. We noted whether these patients received trazodone, quetiapine, or risperidone. We also observed whether they were taking a benzodiazepine receptor agonist, which is a known risk factor. We further examined each patient's age, sex, the department they were visiting, and their diseases. Patients were considered to have taken medication if it was administered within 24 hours before an accidental fall. Multiple logistic regression analysis was used to evaluate the risk of accidental fall. Results: Multivariate analysis showed that the adjusted odds ratios (OR) for each medication (with 95% confidence intervals) were: trazodone (OR, 0.47 [0.27–0.80]), quetiapine (OR, 1.06 [0.46–2.46]), and risperidone (OR, 0.82 [0.41–1.63]). Conclusion: The association of risperidone and quetiapine with accidental falls was unclear. Interestingly, however, trazodone may help reduce the risk, which makes it a potential pharmacologic treatment option for insomnia in patients at high risk for accidental falls. [ABSTRACT FROM AUTHOR]

Antidepressant‐induced jitteriness/anxiety syndrome is characterized as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, and (hypo)mania, which appear immediately after initiation or increased dosage of an antidepressant. This report describes a case of the jitteriness/anxiety syndrome caused by the coadministration of celecoxib with escitalopram and trazodone in a patient with depression and spondylolisthesis. The depression of a patient, a woman in her 60 s, had been in remission at least for 5 years under treatment using escitalopram and trazodone. Immediately after coadministration of celecoxib because of her buttock and limb pain, she showed anxiety, agitation, akathisia, insomnia, irritability, aggressiveness, impulsivity, and hypomania. These symptoms disappeared after the discontinuation of celecoxib. The present case suggests that coadministration of celecoxib with escitalopram and trazodone can cause the jitteriness/anxiety syndrome, presumably via a pharmacokinetic interaction of celecoxib with these antidepressants and/or the effects of celecoxib on serotonergic neurotransmission. [ABSTRACT FROM AUTHOR]

Background: Trazodone is an anxiolytic used PO to decrease anxiety in dogs. Whether or not trazodone affects the neurologic examination in dogs has not been previously reported. Objective: Investigate whether trazodone administration is associated with changes in the neurologic examination in healthy dogs. Animals: Thirty‐two healthy dogs between 1 and 6 years old with no previously diagnosed medical conditions and perceived by their owners as neurologically normal. Methods: Baseline sedation and anxiety assessments and neurologic examination were performed on each dog, followed by trazodone administration (6.25‐8.60 mg/kg PO). The sedation and anxiety assessments and neurologic examination were repeated 2.5 hours after trazodone administration. The examinations were performed by a single board‐certified veterinary neurologist and were video‐recorded. The videos were randomized and reviewed by a different neurologist, blinded to the previous evaluations, who scored the examinations. Results: Seven of 32 (22%) dogs had worse scores on their neurologic examination after receiving trazodone, manifesting as new or progressive PR deficits. Although not clinically relevant, 18.7% of the dogs had consciousness levels that changed from bright, alert, responsive to quiet, alert, responsive after trazodone administration. No other changes were observed on neurologic examination. Sedation and anxiety scores were significantly different after trazodone administration compared to before (P <.001 and P <.001, respectively). Conclusions and Clinical Importance: Most dogs did not have changes on neurologic examination after trazodone administration. However, approximately 20% of dogs had new or worsening PR deficits after receiving trazodone. Ideally, trazodone should not be given before neurologic examination in dogs. [ABSTRACT FROM AUTHOR]

CRISPR‐Cas9–generated zebrafish carrying a 12 base‐pair deletion in stxbpb1b, a paralog sharing 79% amino acid sequence identity with human, exhibit spontaneous electrographic seizures during larval stages of development. Zebrafish stxbp1b mutants provide an efficient preclinical platform to test antiseizure therapeutics. The present study was designed to test antiseizure medications approved for clinical use and two recently identified repurposed drugs with antiseizure activity. Larval homozygous stxbp1b zebrafish (4 days postfertilization (dpf)) were agarose‐embedded and monitored for electrographic seizure activity using a local field recording electrode placed in midbrain. Frequency of ictal‐like events was evaluated at baseline and following 45 min of continuous drug exposure (1 mM, bath application). Analysis was performed on coded files by an experimenter blinded to drug treatment and genotype. Phenytoin (PHT), valproate (VPA), ethosuximide (ESX), levetiracetam (LEV), and diazepam (DZP) had no effect on the ictal‐like event frequency in stxbp1b mutant zebrafish. Clemizole and trazodone decreased ictal‐like event frequency in stxbp1b mutant zebrafish by 80% and 83%, respectively. These results suggest that repurposed drugs with serotonin receptor–binding affinities could be effective antiseizure treatments. Clemizole and trazodone were previously identified in a larval zebrafish model for Dravet syndrome. Based primarily on these preclinical zebrafish studies, compassionate‐use and double‐blind clinical trials with both drugs have progressed. The present study extends this approach to a preclinical zebrafish model representing STXBP1 (syntaxin‐binding protein 1)‐related disorders and suggests that future clinical studies may be warranted. [ABSTRACT FROM AUTHOR]

Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea‐hypopnoea index (AHI) and improve airway collapsibility in patients with obstructive sleep apnoea (OSA). However, some studies have shown that when administered individually, neither noradrenergic or serotonergic agents have been effective at alleviating OSA. This raises the possibility that serotonergic agents (like noradrenergic agents) may also need to be delivered in combination to be efficacious. Therefore, we investigated the effect of an antimuscarinic (oxybutynin) on OSA severity when administered with either duloxetine or milnacipran, two dual noradrenergic/serotonergic reuptake inhibiters. A randomized, double‐blind, 4 way cross‐over, placebo‐controlled trial in ten OSA patients was performed. Patients received each drug condition separately across four overnight in‐lab polysomnography (PSG) studies ~1‐week apart. The primary outcome measure was the AHI. In addition, the four key OSA endotypes (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non‐invasively from the PSGs using validated techniques. There was no significant effect of either drug combinations on reducing the total AHI or improving any of the key OSA endotypes. However, duloxetine+oxybutynin did significantly increase the fraction of hypopnoeas to apnoeas (FHypopnoea) compared to placebo (p = 0.02; d = 0.54). In addition, duloxetine+oxybutynin reduced time in REM sleep (p = 0.009; d = 1.03) which was positively associated with a reduction in the total AHI (R2 = 0.62; p = 0.02). Neither drug combination significantly improved OSA severity or modified the key OSA endotypes when administered as a single dose to unselected OSA patients. [ABSTRACT FROM AUTHOR]

Summary: The European Sleep Research Society (ESRS) has a strong focus on sleep research in Europe. In addition, the ESRS supports sleep medicine in Europe by providing a platform of exchange and communication for the national sleep societies of all European countries and by providing committees that support co‐ordination for important clinical activities. These committees help on clinical guidelines, certification of sleep centres, certification of sleep physicians, psychologists, sleep scientists, sleep technologists, and medical education in sleep medicine. For education in sleep medicine, a "Catalogue on knowledge and skills" has been developed based on a consensus process. This catalogue serves as the backbone for a European textbook on sleep medicine and as the basis for courses, qualifications, and examinations of somnologists in Europe. These activities are devoted to improving and maintain a high quality of care in Europe for sleep medicine services. [ABSTRACT FROM AUTHOR]

Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients' compliance to the antidepressant treatment. A previously verified physiologically‐based pharmacokinetic model based on in vitro and in vivo information on trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO) after single and repeated dosing of the IR formulation and repeated dosing of the OAD formulation in healthy subjects. Receptors included in the simulations were selected using static calculations of RO based on the maximum unbound brain concentration (Cmax,brain,u) of trazodone for each formulation and dosing scheme, resulting in 16 receptors being simulated. Seven receptors were simulated for the IR low dose formulation (30 mg), with similar tonset and duration of coverage (range: 0.09–0.25 h and 2.1–>24 h, respectively) as well as RO (range: 0.64–0.92) predicted between day 1 and day 7 of dosing. The 16 receptors evaluated for the OAD formulation (300 mg) showed high RO (range: 0.97–0.84 for the receptors also covered by the IR formulation and 0.73–0.48 for the remaining) correlating with affinity and similar duration of time above the target threshold to the IR formulation (range: 2–>24 h). The dose‐dependent receptor coverage supports the multimodal activity of trazodone, which may further contribute to its fast antidepressant action and effectiveness in controlling different symptoms in depressed patients. [ABSTRACT FROM AUTHOR]

This article discusses the rare side effect of persistent genital arousal and drug-associated spontaneous orgasms (DASOs) that can occur as a result of trazodone use. While these side effects have been reported in the cisgender population, this case study is one of the first to document them in a transgender patient. The underlying mechanism of action appears to be an augmentation of serotonin neurotransmission. The article emphasizes the importance of clinicians being aware of and inquiring about sexual side effects, especially when working with marginalized or minority patient populations. The definitive treatment for these side effects is discontinuation of the medication. Further research is needed to understand the molecular pathways involved in this phenomenon and its implications for treatment. [Extracted from the article]

Background: Patients with Restless Legs Syndrome (RLS) experience psychological distress and diminished quality of life. Antipsychotics and antidepressants are known to be linked to RLS. Aims: This study aims to investigate the presence of RLS in psychiatric patients who receive antipsychotic and antidepressant drugs and to determine potential risk factors for its occurrence. Methods: Two hundred patients who received antipsychotic and antidepressant drugs for more than 1 month were recruited from two tertiary psychiatric centers in Cairo, Egypt. One hundred apparently healthy volunteers were also included. All patients and controls were screened using the four‐items questionnaire (Arabic version) for RLS. RLS severity was scored according to the validated Arabic version of International Restless Legs Syndrome Study Group rating scale (IRLS). Mimicking conditions were carefully investigated and excluded. Results: Forty‐one percent of the patients who receive antipsychotic and antidepressant drugs were found to have RLS. Family history, past history and smoking are potential risk factors. Trazodone and haloperidol were less associated with RLS. Conclusions: Although limited by its cross‐sectional design, these findings suggest that patients who receive antipsychotic and antidepressant are susceptible to RLS. However, these results need to be replicated on a wider scale. [ABSTRACT FROM AUTHOR]

Aim: To describe the development and acceptability of a decision aid (DA) for chronic insomnia considering discontinuation of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA) hypnotics, and if discontinuing, tapering with or without cognitive behavioral therapy for insomnia (CBT‐I). Methods: We reviewed relevant literature describing chronic insomnia to identify options. We used the results of the systematic review and meta‐analysis conducted previously to determine the related outcomes of two options: discontinuation of BZD/BZRA hypnotics by gradual tapering alone and discontinuation of BZD/BZRA hypnotics by gradual tapering with CBT‐I. We then developed a prototype of DA following the International Patient Decision Aid Standards. A mixed methods survey was conducted to assess the acceptability among patients and healthcare providers. Results: The prototype consisted of a description of insomnia, options of continuing or discontinuing BZD/BRZA hypnotics (if discontinuing, the options of tapering hypnotics with or without CBT‐I), pros and cons of each option, and a value clarification exercise. Patients (n = 24) reported that the DA had acceptable language (79%), adequate information (71%), and well‐balanced presentation (91%). Healthcare providers (n = 20) also provided favorable feedback. Conclusion: We developed a DA for chronic insomnia considering discontinuation of BZD/BRZA hypnotics, which was acceptable for stakeholders. The developed DA was designed to support patients and healthcare providers to make a decision about whether to discontinue BZD/BRZA hypnotics. [ABSTRACT FROM AUTHOR]

Objectives: Evidence in mouse models has found that the antidepressant trazodone may be protective against neurodegeneration. We therefore aimed to compare cognitive decline of people with dementia taking trazodone with those taking other antidepressants. Methods: Three identical naturalistic cohort studies using UK clinical registers. We included all people with dementia assessed during 2008–16 who were recorded taking trazodone, citalopram or mirtazapine for at least 6 weeks. Linear mixed models examined age, time and sex‐adjusted Mini‐mental state examination (MMSE) change in people with all‐cause dementia taking trazodone compared with those taking citalopram and mirtazapine. In secondary analyses, we examined those with non‐vascular dementia; mild dementia; and adjusted results for neuropsychiatric symptoms. We combined results from the three study sites using random‐effects meta‐analysis. Results: We included 2,199 people with dementia, including 406 taking trazodone, with mean 2.2 years follow‐up. There was no difference in adjusted cognitive decline in people with all‐cause or non‐vascular dementia taking trazodone, citalopram or mirtazapine in any of the three study sites. When data from the three sites were combined in meta‐analysis, we found greater mean MMSE decline in people with all‐cause dementia taking trazodone compared to those taking citalopram (0·26 points per successive MMSE measurement, 95% CI 0·03–0·49; p = 0·03). Results in sensitivity analyses were consistent with primary analyses. Conclusions: There was no evidence of cognitive benefit from trazodone compared to other antidepressants in people with dementia in three naturalistic cohort studies. Despite preclinical evidence, trazodone should not be advocated for cognition in dementia. Key points: There is no evidence of cognitive benefit of trazodone in dementiaPeople taking trazodone had worse cognitive decline than those taking citalopramResults were similar in analyses restricted to people with mild dementiaResults were consistent after adjustment for severity of neuropsychiatric symptoms [ABSTRACT FROM AUTHOR]

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings. [ABSTRACT FROM AUTHOR]

Trazodone and cognitive‐behavioural treatment for insomnia (CBT‐I) are widely used to treat patients with chronic insomnia. Although both treatments improve sleep continuity, no study has compared their comparative effectiveness in modifying spectral electroencephalographic (EEG) activity during sleep in humans. In this study, participants included 19 men and women with chronic insomnia who were randomized to either trazodone (n = 8) or CBT‐I (n = 11) treatment for 3 months. We examined delta (0.39–3.91 Hz), theta (4.30–7.81 Hz), alpha (8.20–11.72 Hz), sigma (12.11–14.84 Hz), beta (15.23–35.16 Hz) and gamma (35.55–49.61 Hz) relative power during non‐rapid eye movement (NREM) sleep at pre‐treatment, 3‐ month post‐treatment and 6‐month follow‐up. This study was registered in Clinical Trials (NCT01348542). We found trazodone but not CBT‐I significantly decreased sigma (p =.041, d = 0.88; time × group p =.009) and beta (p =.005, d = 1.41; time × group p =.016) power during NREM sleep at post‐treatment. Compared to CBT‐I, trazodone increased delta (p =.018) and decreased sigma (p =.013) and beta (p =.023) power during NREM sleep at post‐treatment. At follow‐up, we did not observe significant changes in relative EEG power during NREM sleep in either the CBT‐I or trazodone group compared to pre‐treatment. Compared to CBT‐I, trazodone decreased alpha (p =.039) and sigma (p =.009) power during NREM sleep at follow‐up. In conclusion, trazodone, but not CBT‐I, decreased fast‐frequency EEG activity during NREM sleep. Compared to CBT‐I, trazodone appears to have a stronger impact on cortical and physiological hyperarousal in patients with chronic insomnia. [ABSTRACT FROM AUTHOR]

The vast majority of illicit stimulants act at monoaminergic systems, causing both psychostimulant and adverse effects. Stimulants can interact as substrates or antagonists at the nerve terminal monoamine transporter that mediates the reuptake of monoamines across the nerve synaptic membrane and at the vesicular monoamine transporter (VMAT-2) that mediates storage of monoamines in vesicles. Stimulants can act directly at presynaptic or postsynaptic receptors for monoamines or have indirect monoamine-mimetic actions due to the release of monoamines. Cocaine and other stimulants can acutely increase the risk of sudden cardiac death. Stimulants, particularly MDMA, in hot conditions, such as that occurring at a "rave," have caused fatalities from the consequences of hyperthermia, often compounding cardiac adverse actions. This review examines the pharmacology of the cardiovascular and temperature adverse actions of stimulants. [ABSTRACT FROM AUTHOR]

The unfolded protein response has been increasingly implicated as an important pathological pathway and target for therapeutic intervention in neurodegeneration. The licensed antidepressant trazodone is one drug which has been proposed to act on this pathway and may therefore be a potential therapy. Previous examination of existing data for patients with dementia prescribed trazodone did not find a signal suggesting a disease modifying effect. Here we add to that literature by examining the electronic patient record of patients with dementia in Cambridgeshire UK. We found that trazodone is rarely prescribed and where it is used it is at a dose less than half that predicted to be disease modifying. We also found that patients prescribed trazodone had higher levels of neuropsychiatric symptoms and were relatively late in the disease course, likely beyond the optimal point for therapeutic intervention. We suggest it is therefore premature to discard potential therapies based on observational data alone, particularly when experimental medicine approaches to examine the effects of trazodone are feasible. [ABSTRACT FROM AUTHOR]

Background: It has been reported that delirium causes various problems. Many researchers have reported the risk factors associated with the onset of delirium; however, there are few reports focused on persistent delirium. This study aimed to identify the risk factors associated with persistent delirium. Methods: A total of 573 patients hospitalised in Nara Prefecture General Medical Centre from October 2014 through September 2017 who were referred to the psychiatry consultation service were included in this study. Persistent delirium was defined as delirium lasting for 14 days or more. A retrospective study was carried out based on the patients' records. The relationship between various background factors and persistent delirium was statistically analysed. Results: Of the 573 hospitalised patients, 295 were diagnosed as having delirium. Forty‐six patients with persistent delirium and 181 patients with nonpersistent delirium were included in this study. Multivariable logistic regression analyses revealed that male gender, opioid analgesics use, non‐opioid analgesics use, and low serum sodium were significantly and independently associated with persistent delirium. Ramelteon or trazodone was used significantly more in persistent delirium, although each use was not significant. Conclusion: This is the first study to reveal that male gender and use of analgesics were associated with persistent delirium in general hospital. However, as this is a case–control study and may contain bias, future cohort studies and intervention studies are needed. It is also necessary to investigate the relevance of the 'degree of pain' behind the use of analgesics. [ABSTRACT FROM AUTHOR]

Objective: To describe a case of suspected hepatotoxicity in a dog secondary to administration of trazodone. Case Summary: A 6‐year‐old, neutered, mixed breed dog was evaluated for a progressive increased liver enzyme activity over a 6‐week period. The patient originally presented for raisin toxicosis, and hence, was having serial blood work monitoring performed. Trazodone was initially started at that time due to severe separation anxiety while hospitalized (consistently 5 out of 7 days of the week, for a 6‐week duration). Due to continued increased liver enzyme activity, extensive workup was performed which included abdominal ultrasound, leptospirosis titers, bile acids, and liver biopsies. Histopathologic findings were consistent with acute hepatotoxicity. In the absence of other toxicants and the close proximity to drug administration, a drug‐induced hepatopathy secondary to trazodone was presumed. Following discontinuation of trazodone therapy, the hepatopathy completely resolved and the patient fully recovered. New or Unique Information Provided: While acute hepatotoxicity has been reported in human medicine secondary to the administration of trazodone, this is the first reported case of suspected hepatotoxicity in a dog secondary to trazodone therapy. Veterinary professionals should be aware of the rare potential adverse effect that may be seen in canine patients secondary to trazodone therapy. Appropriate clinicopathologic monitoring should occur in patients on chronic trazodone therapy. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone‐matched placebo in 5 periods separated by 7‐day washouts, according to a double‐blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration‐QTc relationship assessed on placebo‐adjusted change from baseline for Fridericia‐corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20‐, 60‐, and 140‐mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60‐ and the 140‐mg doses. Time‐matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin‐validated ECG trial, trazodone had a modest, dose‐dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20‐mg dose and an effect exceeding the values set in E14 guideline with the 60‐ and 140‐mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure. [ABSTRACT FROM AUTHOR]

Pharmacologic and behavioral therapies show comparable response and remission rates as first‐stage treatment for insomnia, with addition of a second‐stage therapy improving outcomes for those who initially do not achieve remission, a randomized trial has found. Treatment sequences that began with behavioral therapies showed the most promising results, the researchers reported. Study results were published online July 8, 2020, in JAMA Psychiatry. [ABSTRACT FROM AUTHOR]

We investigated the prevalence and treatment of patients with chronic insomnia presenting to Swiss primary care physicians (PCPs) part of "Sentinella", a nationwide practice‐based research network. Each PCP consecutively asked 40 patients if they had sleep complaints, documented frequency, duration, comorbidities, and reported ongoing treatment. We analysed data of 63% (83/132) of the PCPs invited. The PCPs asked 76% (2,432/3,216) of included patients about their sleep (51% female); 31% (761/2,432) of these had had insomnia symptoms; 36% (875/2,432) had current insomnia symptoms; 11% (269/2,432) met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) criteria for chronic insomnia (61% female). In all, 75% (201/269) of patients with chronic insomnia had comorbidities, with 49% (99/201) reporting depression. Chronic insomnia was treated in 78% (209/269); 70% (188/268) took medication, 38% (102/268) benzodiazepines or benzodiazepine receptor agonists, 32% (86/268) took antidepressants. Only 1% (three of 268) had been treated with cognitive behavioural therapy for insomnia (CBT‐I). A third of patients presenting for a non‐urgent visit in Swiss primary care reported insomnia symptoms and 11% met the DSM‐5 criteria for chronic insomnia. Hypnotics were the most common treatment, but almost no patients received first‐line CBT‐I. Reducing the burden of insomnia depends on disseminating knowledge about and access to CBT‐I, and encouraging PCPs to discuss it with and offer it as a first‐line treatment to patients with chronic insomnia. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is characterized by dysfunction in motivational, mood‐stress regulation, and sleep systems that interact in complex ways to heighten the risk of relapse during abstinence. Emerging data suggest that excessive and chronic alcohol use disrupts sleep homeostasis and, in abstinence, subjects with AUD are known to experience insomnia that may persist for weeks to years, which we propose to refer to as insomnia associated with alcohol cessation (IAAC). The purpose of this review is to provide an update of pharmacological approaches to therapy including compounds in development, to raise awareness of the prevalence of and unmet need in IAAC and highlight differences in treatment consideration for IAAC as compared to insomnia disorder. We performed a search of select electronic databases to identify studies of pharmacological agents used to treat sleep disturbances in abstinent or treatment‐seeking patients with alcohol use disorder. The search, conducted in June 2019 and updated in December 2019, yielded 1,188 abstracts after duplicates were removed, of which 36 full‐text articles were assessed for eligibility. Eighteen studies were included, 15 randomized controlled trials and three open‐label studies. Several classes of medications including antidepressants, anticonvulsants, and antipsychotics have been evaluated for their effectiveness in treating sleep disturbances in abstinent or treatment‐seeking patients with AUD. None of these medications are approved by the FDA for the treatment of IAAC, and the currently available evidence for these agents is limited. Randomized, controlled clinical trials are warranted to evaluate the efficacy and safety of medications in the treatment of IAAC. [ABSTRACT FROM AUTHOR]

Summary: French general practitioners (GPs) are known to widely prescribe medications to treat insomnia despite their negative effects. GPs' easy access to self‐medication may affect their mental representation of sleep and hypnotics, and subsequently their professional behaviour. Our aim was to examine the association between GPs' personal hypnotic drug consumption habits and their management of patients with sleep disturbances. A randomized sample of Alsatian GPs participated in a survey based on questionnaires including the Pittsburgh Sleep Quality Index, the Dysfunctional Beliefs About Sleep in 10 questions to characterize sleep, and an evaluation of their management strategies regarding sleep for both patients and themselves. Two‐hundred and forty‐nine GPs were included (response rate of 51%). Demographics of the GPs' samples were representative of those of the Alsatian GP population. Fifteen percent of the survey respondents met insomnia criteria. For the management of their own sleep disturbances, 14.3% of GPs were taking hypnotic drugs and 8.7% were taking anxiolytics, with greater drug consumption in the insomnia group. In a multivariate analysis, GPs who personally consumed these medications prescribed significantly more of them to patients, whereas their insomnia status had less impact. Other factors such as gender and type of practice were not associated with a higher prescription rate. Our results indicate that GPs' personal drug consumption can have a significant impact on the management of their patients, therefore suggesting that actions towards GPs' health improvement may also benefit their patients and the public. [ABSTRACT FROM AUTHOR]

The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions‐Severity scale (CGI‐S) score for each subject's AS‐specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school‐aged [4–10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI‐Improvement scale (CGI‐I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or longer. With these medications, many demonstrated significant improvement in sleep disturbances, with no difference in odds of improvement between medications. Disturbed sleep was common in this cohort and significantly worse in younger‐aged participants. The majority received at least one medication trial for disturbed sleep and each of the most commonly prescribed medication was effective for a substantial percentage of participants. Most participants remained on medication for at least 6 months, suggesting favorable tolerability. [ABSTRACT FROM AUTHOR]

There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically‐based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2‐ to 6‐year‐old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6‐ to 12‐year‐old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12‐ to 17‐year‐old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models. [ABSTRACT FROM AUTHOR]

It is not uncommon for depression and sleep disturbances to occur during pregnancy. Trazodone, a triazolopyridine antidepressant that acts primarily as a serotonin (5‐HT) 2 receptor antagonist, is frequently prescribed at lower doses off‐label for the management of insomnia (Nierenberg et al., 1994). [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older. DESIGN: Systematic review and meta‐analysis. SETTING: Specialist or generalist outpatient setting, rehabilitation facility, and nursing facilities. PARTICIPANTS: Persons 65 years and older with MDD. INTERVENTION: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine compared with another antidepressant, placebo, or nonpharmacologic therapy. MEASUREMENTS: Adverse events, arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, QTc prolongation, serious adverse events, and withdrawals due to adverse events. RESULTS: Nineteen randomized controlled trials and two observational studies were included. Most studies evaluated treatment of the acute phase (<12 wk) of MDD of moderate severity. SSRIs led to a statistically similar frequency of overall adverse events vs placebo (moderate strength of evidence [SOE]), but SNRIs caused more overall adverse events vs placebo (high SOE) during the acute treatment phase. Both SSRIs and SNRIs led to more study withdrawals due to adverse events vs placebo (SSRIs low SOE; SNRIs moderate SOE). Duloxetine led to a more falls vs placebo (moderate SOE) during 24 weeks of acute and continuation treatment of MDD. CONCLUSION: In patients 65 years of age or older with MDD, treatment of the acute phase of MDD with SNRIs, but not SSRIs, was associated with a statistically greater number of overall adverse events vs placebo. SSRIs and SNRIs led to a greater number of study withdrawals due to adverse events vs placebo. Duloxetine increased the risk of falls that as an outcome was underreported in the literature. Few studies examined head‐to‐head comparisons, most trials were not powered to evaluate adverse events, and results of observational studies may be confounded. Comparative long‐term studies reporting specific adverse events are needed to inform clinical decision making regarding choice of antidepressants in this population. J Am Geriatr Soc 67:1571–1581, 2019 See related editorial by Lenze and Ajam Oughli [ABSTRACT FROM AUTHOR]

Purpose Systematic studies of the diversion of nonscheduled drugs, except for gabapentin, are not apparent. We searched diversion case reports of all other nonscheduled psychoactive prescription drugs in the Researched Abuse, Diversion, and Addiction‐Related Surveillance (RADARS) System. Methods: Case report data are drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies. Rates of diversion per 100 000 population were calculated for each year from 2002 to 2017 for prescription medications with greater than 400 reported cases during the period. Results: Cyclobenzaprine, quetiapine, and trazodone met criteria for analysis. We found a significant and steady increase in the diversion of each drug over the period. The 2017 annual rates of diversion per 100 000 population for the three medications range from 0.0428 to 0.0726. Although these rates of diversion are much lower than the rate for total opioid analgesics, they are all more than five times higher in 2017 compared with 2002. While diversion rates for opioids have decreased in recent years, rates for cyclobenzaprine, quetiapine, and trazodone have continued to increase. Conclusions: A common attribute of the three nonscheduled drugs studied here is that all are used for the treatment and/or self‐treatment of opioid withdrawal symptoms, and the increasing diversion of these drugs may be related to the ongoing opioid epidemic and to increasing levels of control over pharmaceutical opioid availability in the United States. Prescribers need to be aware of illicit markets for these medications and prescribe to their patients with appropriate caution. [ABSTRACT FROM AUTHOR]

A 4‐year‐old, spayed female French Bulldog was presented for respiratory distress and suspected aspiration pneumonia after oral administration of activated charcoal for possible ingestion of a suspected toxic dose of trazodone. The patient had a moderate volume of pleural effusion, which contained free and intracellular black particulate matter consistent with charcoal. Due to presumed charcoal aspiration with subsequent lung rupture, the right middle and right caudal lung lobes were surgically removed. Histology revealed abundant black debris consistent with charcoal and severe granulomatous inflammation. Based on the clinical, gross, and histologic findings, a diagnosis of severe, chronic, locally extensive, aspiration pneumonia and lung rupture with secondary pleuritis and mediastinitis due to charcoal aspiration was made. Aspiration pneumonia is the main complication of activated charcoal administration, which can incite extensive, granulomatous inflammation in the respiratory tract. To the authors' knowledge, this is the first report describing the cytologic and histologic findings associated with inadvertent charcoal aspiration in a veterinary species. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate whether risk of fall‐related injuries differs between nursing home (NH) residents newly dispensed low‐dose trazodone and those newly dispensed benzodiazepines. Design: Retrospective, matched cohort study in linked, population‐based administrative data. Matching was based on propensity score ( ± 0.2 standard deviations of the score as a caliper), age ( ± 1 year), sex, frailty status, and history of dementia. The derived propensity score included demographic characteristics, clinical comorbidities, cognitive and functional status, and risk factors for falls. Setting: All NHs in Ontario, Canada. Participants: Propensity score–matched pairs of residents aged 66 and older who received a full clinical assessment between April 1, 2010, and March 31, 2015 (N=7,791). Measurements: Hospitalization (emergency department visit or acute care admission) for a fall‐related injury within 90 days of exposure. Subdistribution hazard functions accounted for competing risk of death. Sensitivity analyses were used to examine falls resulting in hip or wrist fracture only, as well as different lengths of follow‐up at 30, 60, and 180 days. Results: Cumulative incidence of a fall‐related injury in the 90 days after index was 5.7% for low‐dose trazodone users and 6.0% for benzodiazepine users (between‐group change=–0.29, 95% confidence interval (CI)=–1.02–0.44]; hazard ratio=0.94, 95% CI=0.83–1.08). Findings were consistent across sensitivity analyses. Conclusion: New use of low‐dose trazodone was no safer with respect to a risk of a fall‐related injury than new use of benzodiazepines. Additional studies to compare the effectiveness and risks of low‐dose trazodone with those of a variety of psychotropic drug therapies are required in light of increasing trends in the use of trazodone in NHs. [ABSTRACT FROM AUTHOR]

Trazodone is a serotonin receptor antagonist and reuptake inhibitor used extensively as an anxiolytic in human and small animal veterinary medicine. The aims of this study were to determine the pharmacokinetics of oral trazodone in experimental horses and to evaluate the effect of oral trazodone in clinical horses. Six experimental horses were administered trazodone at 7.5 or 10 mg/kg. Plasma concentrations of trazodone and its metabolite (m‐CPP) were determined via UPLC‐MS/MS. Noncompartmental pharmacokinetic analysis, sedation and ataxia scores were determined. Trazodone was rapidly absorbed after oral administration with a maximum concentration of 2.5–4.1 μg/ml and half‐life of the terminal phase of approximately 7 hr. The metabolite was present at low levels in all horses, representing only 2.5% of the total area under the curve. In experimental horses, concentration‐dependent sedation and ataxia were noted, lasting up to 12 hr. For clinical cases, medical records of horses treated with trazodone for various abnormal behaviours were reviewed and data were summarized. Trazodone was successful in modifying behavioural problems to some degree in 17 of 18 clinical cases. Tolerance and subsequent lack of drug effect occurred in two of 18 clinical cases following 14 or 21 days of use. In both populations of horses, adverse effects attributed to trazodone include oversedation, muscle fasciculations and transient arrhythmias. [ABSTRACT FROM AUTHOR]

Burning mouth syndrome (BMS) is a chronic oral pain syndrome that primarily affects peri‐ and postmenopausal women. It is characterized by oral mucosal burning and may be associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. The etiology of the disease process is unknown, but is thought to be neuropathic in origin. The goal of this systematic review was to assess the efficacy of the various treatments for BMS. Literature searches were conducted through PubMed, Web of Science, and Cochrane Library databases, which identified 22 randomized controlled trials. Eight studies examined alpha‐lipoic acid (ALA), three clonazepam, three psychotherapy, and two capsaicin, which all showed modest evidence of potentially decreasing pain/burning. Gabapentin was seen in one study to work alone and synergistically with ALA. Other treatments included vitamins, benzydamine hydrochloride, bupivacaine, Catuama, olive oil, trazodone, urea, and Hypericum perforatum. Of these other treatments, Catuama and bupivacaine were the only ones with significant positive results in symptom improvement. ALA, topical clonazepam, gabapentin, and psychotherapy may provide modest relief of pain in BMS. Gabapentin may also boost the effect of ALA. Capsaicin is limited by its side effects. Catuama showed potential for benefit. Future studies with standardized methodology and outcomes containing more patients are needed. [ABSTRACT FROM AUTHOR]

A new sensitized chemiluminescence method by acidic permanganate oxidation was developed for the sensitive determination of trazodone. A fluorescent dye as used rhodamine 6G to increase a chemiluminescence intensity. Under optimum conditions, the liner range of the calibration curve was obtained for 1-5000 nmol/L. The limit of detection was calculated from 3σ of a blank was 0.23 nmol/L. The coexistent ions and substances had no interference with the chemiluminescence measurement. The chemiluminescence spectra were measured to elucidate a possible mechanism for the system. The present method was satisfactorily used in the determination of the drugs in pharmaceutical samples and animal serums. [ABSTRACT FROM AUTHOR]

ABSTRACT It has been reported that the bioactive intermediate metabolites of trazodone might cause hepatotoxicity. This study was designed to investigate the exact mechanism of hepatocellular injury induced by trazodone as well as the protective effects of taurine and/or melatonin against this toxicity. Freshly isolated rat hepatocytes were used. Trazodone was cytotoxic and caused cell death with LC50 of 300 µm within 2 h. Trazodone caused an increase in reactive oxygen species (ROS) formation, malondialdehyde accumulation, depletion of intracellular reduced glutathione (GSH), rise of oxidized glutathione disulfide (GSSG), and a decrease in mitochondrial membrane potential, which confirms the role of oxidative stress in trazodone-induced cytotoxicity. Preincubation of hepatocytes with taurine prevented ROS formation, lipid peroxidation, depletion of intracellular reduced GSH, and increase of oxidized GSSG. Taurine could also protect mitochondria against trazodone-induced toxicity. Administration of melatonin reduced the toxic effects of trazodone in isolated rat hepatocytes. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:457-462, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21509 [ABSTRACT FROM AUTHOR]

Objective This study aimed to evaluate the effects of repeated treatments with the sedative antidepressants mirtazapine and trazodone on driving performance and cognitive function. Methods Nineteen healthy men received continuous nocturnal doses of 15-mg mirtazapine , 25-mg trazodone, or placebo for 8 days in a double-blinded, three-way crossover trial. Subjects were asked to perform three driving tasks (road tracking, car following, and harsh braking) using a driving simulator and cognitive tasks (the Wisconsin Card Sorting Test, Continuous Performance Test, and N-back Test) at baseline and on Days 2 and 9. Stanford Sleepiness Scale scores were also assessed. Results Mirtazapine significantly increased the standard deviation of lateral position in the road-tracking task as compared with trazodone on Day 2. Mirtazapine significantly increased Stanford Sleepiness Scale scores as compared with trazodone and placebo. For the remaining tasks, no significant effects of treatment were observed. Conclusions Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations. Both initial sedative effects and pharmacological profiles should be taken into consideration when using sedative antidepressants. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]