A green micelle-enhanced first derivative synchronous fluorescence approach for determination of donepezil HCl and trazodone HCl in their pure state, pharmaceutical dosage form and spiked human plasma.

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.

Acute exposure and biomarkers assessment in rainbow trout exposed to selected pharmaceuticals.

Pharmaceuticals released from municipal effluents discharges pose a risk to aquatic organisms. The toxicity of 5 pharmaceuticals with distinct therapeutic actions were assessed in rainbow trout: olanzapine (antipsychotic), erythromycin (antibiotic), mycophenoate (immunosuppression), pinaverium (anti-inflammatory) and trazodone (sedative). Juveniles were exposed to these drugs for 96 h at concentrations between 64 µg/L up to 40 mg/L to reach lethality. Survival was determined and a suite of biomarkers was analyzed for drug biotransformation, oxidative stress/damage and metabolic activity at sublethal concentrations. The data revealed the following toxicity: olanzapine >trazodone>mycophenolate>pinaverium∼erythromycin based on mortality. The data also revealed that toxicity was associated to mass, pKa and hydrophobicity and the following sublethal effects: GST, LPO and DNA strand breaks. Pharmaceuticals with lower molecular weight, physiological pKa, moderate hydrophobicity, low biotransformation and DNA strand breaks were generally more toxic to fish. However, this should be considered as a general guide in identifying toxic pharmaceuticals in non-target organisms.

Pharmacological interventions to improve sleep in people with Alzheimer's disease: a meta-analysis of randomized controlled trials.

INTRODUCTION: This systematic review and meta-analysis evaluates the evidence from randomized controlled trials (RCTs) involving pharmacological interventions for improving sleep in people with Alzheimer's disease (AD). METHODS: A systematic literature search in eight databases from January 2000 to July 2023 focusing on RCTs that compared a pharmacological intervention with a placebo for enhancing sleep in people with AD. The authors registered the study protocol at Prospero, followed the PRISMA guidelines, and produced the pooled estimates using random-effect or IVhet models. RESULTS: Eight different interventions and 29 different sleep outcomes were examined in 14 RCTs included in this review. Eszopiclone positively affected sleep efficiency, as did orexin antagonists. However, there was no difference when melatonin was used. The interventions demonstrated low discontinuation rates and a few adverse drug reactions. CONCLUSION: Although melatonin was the most investigated intervention, the evidence for its efficacy is inconclusive. On the other hand, trazodone and orexin receptor antagonists showed promising results; however, more RCTs are needed for definite answers.

Effectiveness of Antidepressants in Combination with Psychotherapy.

BACKGROUND: Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no specific advice on which antidepressant is best for a given medical history. AIMS OF THE STUDY: For patients with major depression who are in psychotherapy, this study provides an empirically derived guideline for prescribing antidepressant medications that fit patients' medical history. METHODS: This retrospective, observational, cohort study analyzed a large insurance database of 3,678,082 patients. Data was obtained from healthcare providers in the U.S. between January 1, 2001, and December 31, 2018. These patients had 10,221,145 episodes of antidepressant treatments. This study reports the remission rates for the 14 most commonly prescribed single antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine) and a category named "Other" (other antidepressants/combination of antidepressants). The study used robust LASSO regressions to identify factors that affected remission rate and clinicians' selection of antidepressants. The selection bias in observational data was removed through stratification. We organized the data into 16,770 subgroups, of at least 100 cases, using the combination of the largest factors that affected remission and selection bias. This paper reports on 2,467 subgroups of patients who had received psychotherapy. RESULTS: We found large, and statistically significant, differences in remission rates within subgroups of patients. Remission rates for sertraline ranged from 4.5% to 77.86%, for fluoxetine from 2.86% to 77.78%, for venlafaxine from 5.07% to 76.44%, for bupropion from 0.5% to 64.63%, for desvenlafaxine from 1.59% to 75%, for duloxetine from 3.77% to 75%, for paroxetine from 6.48% to 68.79%, for escitalopram from 1.85% to 65%, and for citalopram from 4.67% to 76.23%. Clearly these medications are ideal for patients in some subgroups but not others. If patients are matched to the subgroups, clinicians can prescribe the medication that works best in the subgroup. Some medications (amitriptyline, doxepin, nortriptyline, and trazodone) always had remission rates below 11% and therefore were not suitable as single antidepressant therapy for any of the subgroups. DISCUSSIONS: This study provides an opportunity for clinicians to identify an optimal antidepressant for their patients, before they engage in repeated trials of antidepressants. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: To facilitate the matching of patients to the most effective antidepressants, this study provides access to a free, non-commercial, decision aid at http://MeAgainMeds.com. IMPLICATIONS FOR HEALTH POLICIES:  Policymakers should evaluate how study findings can be made available through fragmented electronic health records at point-of-care. Alternatively, policymakers can put in place an AI system that recommends antidepressants to patients online, at home, and encourages them to bring the recommendation to their clinicians at their next visit. IMPLICATIONS FOR FURTHER RESEARCH:  Future research could investigate (i) the effectiveness of our recommendations in changing clinical practice, (ii) increasing remission of depression symptoms, and (iii) reducing cost of care. These studies need to be prospective but pragmatic. It is unlikely random clinical trials can address the large number of factors that affect remission.

Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-Analysis.

Importance: Antipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA. Objective: To compare the efficacy associated with AIA treatments. Data Sources: Three databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023. Study Selection: Selected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded. Data Extraction and Synthesis: Data extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. Main Outcomes and Measures: The primary outcome was the severity of akathisia measured by a validated scale at the last available end point. Results: Fifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, -1.20; 95% CI, -1.83 to -0.58), biperiden (6 mg/d for ≥14 days; SMD, -1.01; 95% CI, -1.69 to -0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, -0.92; 95% CI, -1.57 to -0.26), trazodone (50 mg/d for ≥5 days; SMD, -0.84; 95% CI, -1.54 to -0.14), mianserin (15 mg/d for ≥5 days; SMD, -0.81; 95% CI, -1.44 to -0.19), and propranolol (20 mg/d for ≥6 days; SMD, -0.78; 95% CI, -1.35 to -0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found. Conclusions and Relevance: In this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

Effect of lipid emulsion on neuropsychiatric drug-induced toxicity: A narrative review.

Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.

Psychiatric comorbidities and prescribing tendencies of sleep medications and related medications in young people with insomnia: a United States commercial claims-based analysis.

STUDY OBJECTIVES: To characterize children and youth newly diagnosed with insomnia and to describe their use of sleep and other related prescription medications. METHODS: Within a commercial claims database (January 1, 2016-December 31, 2021), we identified children and youth (2-24 years) with a newly recorded insomnia diagnosis (G47.0x; F51.0x) and examined psychiatric diagnoses in the prior 6 months. We evaluated sleep and related prescription medications dispensed in the week after new insomnia diagnoses (i.e. trazodone, other antidepressants, hydroxyzine, alpha-agonists, benzodiazepines, non-benzodiazepine hypnotics "z-drugs," antipsychotics, and others). Analyses were stratified by age and psychiatric comorbidities. RESULTS: Among 68 698 children and 108 118 older youth (18-24 years) with a new insomnia diagnosis, three-quarters had a diagnosed comorbid psychiatric condition; anxiety disorders, depression, and ADHD were the most common. Among those without comorbid psychiatric diagnoses, 20.2% of children and 37.4% of older youth had a sleep or related medication dispensed in the following week. In children without a comorbid psychiatric diagnosis, alpha-agonists, hydroxyzine, and trazodone were the most common medications; in older youth, trazodone was the most common medication followed by hydroxyzine, z-drugs, and SSRIs. Sleep and related prescription medications were more commonly dispensed to those with psychiatric comorbidities. From 2017 to 2021, there was an increase in hydroxyzine prescriptions following a new insomnia diagnosis and decline in z-drug and benzodiazepine prescriptions. CONCLUSIONS: Our findings from a nationwide sample of young people with insomnia highlight the high prevalence of psychiatric comorbidities and variety of sleep and related medications they receive. Characterizing prescribing tendencies informs guideline development and future research.

The effects of selected sedatives on basal and stimulated serum cortisol concentrations in healthy dogs.

Background: Hormone assessment is typically recommended for awake, unsedated dogs. However, one of the most commonly asked questions from veterinary practitioners to the endocrinology laboratory is how sedation impacts cortisol concentrations and the adrenocorticotropic hormone (ACTH) stimulation test. Butorphanol, dexmedetomidine, and trazodone are common sedatives for dogs, but their impact on the hypothalamic-pituitary-adrenal axis (HPA) is unknown. The objective of this study was to evaluate the effects of butorphanol, dexmedetomidine, and trazodone on serum cortisol concentrations. Methods: Twelve healthy beagles were included in a prospective, randomized, four-period crossover design study with a 7-day washout. ACTH stimulation test results were determined after saline (0.5 mL IV), butorphanol (0.3 mg/kg IV), dexmedetomidine (4 µg/kg IV), and trazodone (3-5 mg/kg PO) administration. Results: Compared to saline, butorphanol increased basal (median 11.75 µg/dL (range 2.50-23.00) (324.13 nmol/L; range 68.97-634.48) vs 1.27 µg/dL (0.74-2.10) (35.03 nmol/L; 20.41-57.93); P < 0.0001) and post-ACTH cortisol concentrations (17.05 µg/dL (12.40-26.00) (470.34 nmol/L; 342.07-717.24) vs 13.75 µg/dL (10.00-18.90) (379.31 nmol/L; 275.96-521.38); P ≤ 0.0001). Dexmedetomidine and trazodone did not significantly affect basal (1.55 µg/dL (range 0.75-1.55) (42.76 nmol/L; 20.69-42.76); P = 0.33 and 0.79 µg/dL (range 0.69-1.89) (21.79 nmol/L; 19.03-52.14); P = 0.13, respectively, vs saline 1.27 (0.74-2.10) (35.03 nmol/L; 20.41-57.93)) or post-ACTH cortisol concentrations (14.35 µg/dL (range 10.70-18.00) (395.86 nmol/L; 295.17-496.55); (P = 0.98 and 12.90 µg/dL (range 8.94-17.40) (355.86 nmol/L; 246.62-480); P = 0.65), respectively, vs saline 13.75 µg/dL (10.00-18.60) (379.31 nmol/L; 275.86-513.10). Conclusion: Butorphanol administration should be avoided prior to ACTH stimulation testing in dogs. Further evaluation of dexmedetomidine and trazodone's effects on adrenocortical hormone testing in dogs suspected of HPA derangements is warranted to confirm they do not impact clinical diagnosis.

Analysis of Factors Affecting Concentrations and Concentration-To-Dose Ratios of Trazodone.

BACKGROUND: Trazodone is prescribed for several clinical conditions. Multiple factors may affect trazodone to reach its therapeutic reference range. The concentration-to-dose (C/D) ratio can be used to facilitate the therapeutic drug monitoring of trazodone. The study aimed to investigate factors on the concentrations and C/D ratio of trazodone. METHODS: This study analyzed the therapeutic drug monitoring electronic case information of inpatients in the First Hospital of Hebei Medical University from October 2021 to July 2023. Factors that could affect the concentrations and C/D ratio of trazodone were analyzed, including body mass index, sex, age, smoking, drinking, drug manufacturers, and concomitant drugs. RESULTS: A total of 255 patients were analyzed. The mean age was 52.44 years, and 142 (55.69%) were women. The mean dose of trazodone was 115.29 mg. The mean concentration of trazodone was 748.28 ng/mL, which was in the therapeutic reference range (700-1000 ng/mL). 50.20% of patients reached the reference range, and some patients (36.86%) had concentrations below the reference range. The mean C/D ratio of trazodone was 6.76 (ng/mL)/(mg/d). A significant positive correlation was found between daily dose and trazodone concentrations (r 2 = 0.2885, P < 0.001). Trazodone concentrations were significantly affected by dosage, sex, smoking, drinking, and concomitant drugs of duloxetine or fluoxetine. After dosage emendation, besides the above factors, it was influenced by age ( P < 0.05, P < 0.01, or P < 0.001). CONCLUSIONS: This study identified factors affecting trazodone concentrations and C/D ratio. The results can help clinicians closely monitor patients on trazodone therapy and maintain concentrations within the reference range.

Effectiveness of Existing Insomnia Therapies for Patients Undergoing Hemodialysis : A Randomized Clinical Trial.

BACKGROUND: Chronic insomnia is common in patients undergoing in-center hemodialysis, yet there is limited evidence on effective treatments for this population. OBJECTIVE: To compare the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), trazodone, and placebo for insomnia in patients undergoing long-term hemodialysis. DESIGN: Randomized, multicenter, double-blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT03534284). SETTING: 26 dialysis units in Albuquerque, New Mexico, and Seattle, Washington. PARTICIPANTS: Patients with Insomnia Severity Index (ISI) score of 10 or greater, with sleep disturbances on 3 or more nights per week for 3 or more months. INTERVENTION: Participants were randomly assigned to 6 weeks of CBT-I, trazodone, or placebo. MEASUREMENTS: The primary outcome was the ISI score at 7 and 25 weeks from randomization. RESULTS: A total of 923 patients were prescreened, and of the 411 patients with chronic insomnia, 126 were randomly assigned to CBT-I (n = 43), trazodone (n = 42), or placebo (n = 41). The change in ISI scores from baseline to 7 weeks with CBT-I or trazodone was no different from placebo: CBT-I, -3.7 (95% CI, -5.5 to -1.9); trazodone, -4.2 (CI, -5.9 to -2.4); and placebo, -3.1 (CI, -4.9 to -1.3). There was no meaningful change in ISI scores from baseline to 25 weeks: CBT-I, -4.8 (CI, -7.0 to -2.7); trazodone, -4.0 (CI, -6.0 to -1.9); and placebo, -4.3 (CI, -6.4 to -2.2). Serious adverse events (SAEs), particularly serious cardiovascular events, were more frequent with trazodone (annualized cardiovascular SAE incidence rates: CBT-I, 0.05 [CI, 0.00 to 0.29]; trazodone, 0.64 [CI, 0.34 to 1.10]; and placebo, 0.21 [CI, 0.06 to 0.53]). LIMITATION: Modest sample size and most participants had mild or moderate insomnia. CONCLUSION: In patients undergoing hemodialysis with mild or moderate chronic insomnia, there was no difference in the effectiveness of 6 weeks of CBT-I or trazodone compared with placebo. The incidence of SAEs was higher with trazodone. PRIMARY FUNDING SOURCE: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Solriamfetol and m-chlorophenylpiperazine cause false positive amphetamine results on urine drug screening.

Urine drug screening by immunoassay is a common method to quickly identify drug exposures in the emergency setting and to detect unexpected drug exposures in a variety of patient care and occupational health settings. Although they provide rapid results, immunoassays are susceptible to cross-reactivity with other medications and metabolites. Herein we evaluate the performance of the Thermo Scientific DRI Amphetamines immunoassay for reactivity with trazodone, aripiprazole, atomoxetine, solriamfetol and relevant metabolites. Each of these compounds were spiked into drug-free urine across a range of concentrations and assessed for positivity on amphetamine screen. We demonstrate that the Thermo Scientific DRI assay is susceptible to interferences from m-chlorophenylpiperazine (mCPP), the main metabolite of trazodone, and solriamfetol. Characterization of assay-specific interferences in toxicology screening is instrumental for accurate interpretation of toxicology results, evaluation of patients in emergent settings and supporting patient care.

The impact of single-dose trazodone administration on plasma endogenous adrenocorticotropic hormone and serum cortisol concentrations in healthy dogs.

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.

Influence of a single oral dose of trazodone on intradermal histamine reactivity in clinically healthy dogs.

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.

Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.

The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway-including by the licensed drug, trazodone-restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measure de novo protein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant nascent proteome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just 2 weeks largely restored the whole disease nascent proteome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wild-type levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.

Effects of trazodone and dexmedetomidine on fentanyl-mediated reduction of isoflurane minimum alveolar concentration in cats.

OBJECTIVE: To screen modulators of biogenic amine (BA) neurotransmission for the ability to cause fentanyl to decrease isoflurane minimum alveolar concentration (MAC) in cats, and to test whether fentanyl plus a combination of modulators decreases isoflurane MAC more than fentanyl alone. STUDY DESIGN: Prospective, experimental study. ANIMALS: A total of six adult male Domestic Short Hair cats. METHODS: Each cat was anesthetized in three phases with a 1 week washout between studies. In phase 1, anesthesia was induced and maintained with isoflurane, and MAC was measured in duplicate using a tail clamp stimulus and standard bracketing technique. A 21 ng mL-1 fentanyl target-controlled infusion was then administered and MAC measured again. In phase 2, a single cat was administered a single BA modulator (buspirone, haloperidol, dexmedetomidine, pregabalin, ramelteon or trazodone) in a pilot drug screen, and isoflurane MAC was measured before and after fentanyl administration. In phase 3, isoflurane MAC was measured before and after fentanyl administration in cats co-administered trazodone and dexmedetomidine, the two BA modulator drugs associated with fentanyl MAC-sparing in the screen. Isoflurane MAC-sparing by fentanyl alone, trazodone-dexmedetomidine and trazodone-dexmedetomidine-fentanyl was evaluated using paired t tests with p < 0.05 denoting significant effects. RESULTS: The MAC of isoflurane was 1.87% ± 0.09 and was not significantly affected by fentanyl administration (p = 0.09). In the BA screen, cats administered trazodone or dexmedetomidine exhibited 26% and 22% fentanyl MAC-sparing, respectively. Trazodone-dexmedetomidine co-administration decreased isoflurane MAC to 1.50% ± 0.14 (p < 0.001), and the addition of fentanyl further decreased MAC to 0.95% ± 0.16 (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl alone does not affect isoflurane MAC in cats, but co-administration of trazodone and dexmedetomidine causes fentanyl to significantly decrease isoflurane requirement.

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study.

STUDY OBJECTIVES: we aimed to compare the effects of atomoxetine and trazodone (A-T) in combination with placebo in patients with obstructive sleep apnea (OSA). METHODS: This randomized, placebo-controlled, double-blind, crossover trial study was conducted in adults with OSA referred to a Sleep Clinic. Participants with eligibility criteria were recruited. Patients were studied on two separate nights with one-week intervals, once treated with trazodone (50 mg) and atomoxetine (80 mg) combination and then with a placebo and the following polysomnography tests. RESULTS: A total of 18 patients with OSA completed the study protocol, 9(50%) were male, the mean age was 47.5 years (SD = 9.8) and the mean Body mass index of participants was 28.4 kg/m2 (SD = 3.4). Compared with the placebo, the A-T combination resulted in significant differences in AHI (28.3(A-T) vs. 42.7 (placebo), p = 0.025), duration of the REM stage (1.3%TST (A-T) vs. 13.1%TST (placebo), p = 0.001), and the number of REM cycles (0.8 (A-T) vs. 4.7 (placebo), p = 0.001), number of apneas (38.3 (A-T) vs. 79.3 (placebo), p = 0.011), number of obstructive apneas (37.2 (A-T) vs. 75.2 (placebo), p = 0.011), oxygen desaturation index (29.5 (A-T) vs. 42.3 (placebo), p = 0.022) and number of respiratory arousals (43.2 (A-T) vs. 68.5 (placebo), p = 0.048). This decrement effect did not change among those with a low-arousal phenotype of OSA. CONCLUSIONS: The A-T combination significantly improved respiratory events' indices compared with placebo in patients with OSA. This combination is recommended to be assessed in a large trial. It could be an alternative for those who do not adhere to the standard available treatments for OSA.

Estudio de mortalidad de pacientes en tratamiento con digoxina y trazodona / Study of mortality on patients with digoxin and trazodone treatment

Objetivos: Analizar la influencia de trazodona en la mortalidad de pacientes en tratamiento con digoxina. Material y métodos: Estudio observacional retrospectivo comparativo de mortalidad de pacientes en tratamiento concomitante con digoxina y trazodona versus digoxina. El período de estudio fue de un año (1 de mayo de 2020 hasta 30 de abril de 2021). Las variables recogidas fueron edad, sexo, indicación, dosis de digoxina y trazodona, fecha de inicio de trazodona, fecha fin de digoxina y trazodona, número total de fármacos prescritos, éxitus y fecha de éxitus. El análisis estadístico se realizó mediante la aplicación Stata®. Versión 14.2. Resultados: Se incluyeron 644 pacientes en tratamiento con digoxina, 73 en el grupo con trazodona y 571 en el grupo sin trazodona. Al final del periodo estudiado se registraron 73 muertes, observándose una mortalidad del 34,3% en el grupo de digoxina y trazodona, y del 8,4% en el grupo de digoxina. Las variables relacionadas con el riesgo de muerte fueron tratamiento con tradozona, edad y número de tratamientos prescritos. Conclusiones: Los resultados del estudio sugieren un incremento del riesgo de mortalidad en pacientes de edad avanzada en tratamiento con digoxina y trazodona. La falta de evidencia de uso de trazodona como hipnótico, la interacción farmacocinética entre ambos fármacos y el perfil de seguridad de trazodona, hace necesario una estrecha monitorización de los pacientes o valorar alternativas con mayores evidencias de seguridad.(AU)

Objectives: To evaluate the trazodone influence on the mortality of patients treated with digoxin. Material and methods: Retrospective, observational, comparative study that included patients receiving trazodone and digoxin concomitantly and patients on digoxin treatment without trazodone between April 2020-April 2021. Age, sex, drug indication, digoxin and trazodone dosage, start and end dates of trazodone use, digoxin end date, number of prescribed drugs and death date were the variables we paid attention to. Statistical analysis was performed using the Stata® application. Version 14.2. Results: 644 patients were included, 73 in the group digoxin with trazodone and 571 in the group without trazodone. At the end of the study period, 73 deaths were recorded. Mortality in the digoxin and trazodone group were 34.3% and 8.4% in the digoxin group. The variables related to the risk of death were treatment with trazodone, age and number of prescribed treatments. Conclusions: The results of the study suggest an increased risk of mortality in elderly patients in treated with digoxin and trazodone. The lack of evidence in the use of trazodone as a hypnotic, the pharmacokinetic interaction between both drugs and the safety profile of trazodone, makes it necessary to closely monitor patients or assess therapeutic alternatives with more evidence to be sure its use is safe.(AU)

Treatment of REM sleep behavior disorder with trazodone: report of 3 cases.

Rapid eye movement sleep behavior disorder is a sleep disturbance characterized by the absence of regular paralysis during rapid eye movement sleep, accompanied by dream enactment behavior. The available pharmacotherapy options for treating rapid eye movement sleep behavior disorder are limited, and the utilization of antidepressants has yielded mixed results. We report 3 cases of isolated rapid eye movement sleep behavior disorder improved with trazodone. Doses of 50-100 mg of trazodone at bedtime over 4-6 months resulted in significant clinical improvement. These cases highlight that trazodone could serve as a treatment for isolated rapid eye movement sleep behavior disorder that does not respond to traditional treatments at submaximal dosages. CITATION: Barrow J, Vendrame M. Treatment of REM sleep behavior disorder with trazodone: report of 3 cases. J Clin Sleep Med. 2024;20(5):821-823.