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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: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. Methods: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. Results: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were − 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, − 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, − 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, − 1.92 ± 2.21 in Gaba group, and − 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) − 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI − 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI − 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI − 1.6648, − 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. Conclusions: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. Clinical Trial Registration: NCT03749642. [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 efficacy of trazodone for several psychopathologic dimensions of depression has been shown in the literature. Trazodone has been widely used in some clinical contexts (e.g. for insomnia and depression in the elderly). However, the role of trazodone in several aspects of depression is not well known. Eight experts from academic and medical centers across Italy met to identify the difficulties and barriers faced in daily clinical practice in the assessment and management of major depressive disorder and how the use of trazodone could address some unmet needs. The objective of the expert meetings and the present document was to increase knowledge of particular areas of treatment with trazodone. Evidence of the role of trazodone in patients affected by major depressive disorder with anxiety symptoms, insomnia, agitation, cognitive deficits, alcohol use disorders, physical comorbidities, and suicide risk has been identified, showing the effectiveness of trazodone in different presentations of major depressive disorder. The main characteristics of patients with depression for whom trazodone seems to be most effective have been identified, providing clinicians with information on possible uses of this drug in such population of patients. [ABSTRACT FROM AUTHOR]

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.

Abstract Introduction Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. Methods This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) − 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI − 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI − 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI − 1.6648, − 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. Conclusions The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. Clinical Trial Registration NCT03749642.

Abstract Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD.

Background: It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice. Methods: One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = "unfamiliar"; 1 = "familiar") and how they managed insomnia using a nine-point Likert scale (1 = "I never prescribe/perform it"; 9 = "I often prescribe/perform it"). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it. Results: Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8–5.4 points and 4.0–4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5–1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48–74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points. Conclusion: This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists. [ABSTRACT FROM AUTHOR]

A sensitive spectrofluorimetric method was developed to determine trazodone hydrochloride in its formulation and urine sample. The principle of the developed method is based on the formation of an ion pair complex at a pH of 4.27 between the analyte drug and eosin Y, followed by its extraction into dichloromethane and subsequent fluorescence measurement. The fluorescence of the extracted trazodone-eosin Y complex was recorded at 450 nm with an excitation wavelength of 350 nm. Recording the fluorescence was utilized to construct the calibration plot, which was found to be linear in the range of 32.0–1.50 × 103 ng/mL of trazodone hydrochloride. The influences of experimental variables, namely pH, volumes of eosin Y (2.90 × 10–3 M), and buffer solution (pH 4.27), on the fluorescence intensity were examined and optimized by response surface methodology via Box−Behnken design. The limits of detection and the limit of quantitation of the reported method are 9.50 and 28.79 ng/mL, respectively. The accuracy of the proposed method was evaluated for intra-day and inter-day precision in the range of 0.46 to 0.77% RSD. The content of trazodone hydrochloride in its dosage forms was determined by the developed method using the standard addition technique, and the results showed good recovery between 96.50 and 99.25%, with a standard analytical error of 1.54 × 10–5 to 2.86 × 10–4. Interval hypothesis testing confirmed that it is lower than ±2%; hence, there was no bias between the developed and reference methods. No interference was observed from the common excipients present in tablet formulations. The developed method was also successfully applied for the determination of trazodone in urine samples, and recovery of the drug was observed in the range of 90–98%. [ABSTRACT FROM AUTHOR]

The antidepressant drug trazodone (TRZ) is commonly used for treating depression, anxiety, and insomnia, however, it causes cardiotoxicity, which is one of its limitations. The objective of this work was to investigate the impact of sage (Salvia officinalis) in rats against cardiotoxicity induced by TRZ and to investigate the mechanisms involved in its cardio-protective properties through autophagy and oxidative stress. Fifty male albino rats were split randomly into five experimental groups: control group, sage oil group (100 mg/kg), TRZ group (20 mg/kg), protective group, and curative group. Cardiac function biomarkers (aspartate aminotransferase [AST], creatine kinase-MB [CK-MB], and cardiac troponin T [cTnI]) were assessed in serum. Oxidative stress and inflammatory biomarkers in cardiac tissue (total antioxidant capacity, malondialdehyde, and tumor necrosis factor-α) were evaluated. Heart tissues were subjected to histological, immunohistochemical, and ultrastructural evaluations. DNA damage also evaluated. Significant rise in the levels of AST, CK-MB, and cTnI were observed with enhanced autophagy along with marked histopathological changes in the form of interrupted muscle fibers with wide interstitial spaces with areas of hemorrhage and extravasated blood and interstitial mononuclear cellular infiltration in TRZ group. DNA damage was also significantly increased in TRZ group. However, administration of sage in both protective and curative groups show marked improvement of the cardiac alterations. In conclusion, sage ameliorated the alterations in the heart induced by trazadone through modulation of autophagy and oxidative stress. [ABSTRACT FROM AUTHOR]

The article offers information on the use of trazodone for insomnia and other sleep disturbances, highlighting its common prescription despite being an off-label use. Topics include the challenges of non-pharmacological options like cognitive behavioral therapy for insomnia (CBT-I) in rural areas, the limitations of sleep hygiene education, and the need for immediate sleep solutions in some cases.

Sleep disorders are one of the most common acute reactions on the plateau, which can cause serious complications. However, there is no effective and safe treatment currently available. Nimodipine (NMD) is a dihydropyridine calcium channel blocker with neuroprotective and vasodilating activity, mainly used for the treatment of ischemic brain injury. Commercial oral or injectable NMD formulations are not a good option for central neuron diseases due to their poor brain delivery. In this study, nimodipine dissolving microneedles (NDMNs) were prepared for the prevention of sleep disorders caused by hypoxia. NDMNs were composed of NMD and polyvinyl pyrrolidone (PVP) K90 with a conical morphology and high rigidity. After administration of NDMNs on the back neck of mice, the concentration of NMD in the brain was significantly higher than that of oral medication as was confirmed by the fluorescent imaging on mouse models. NDMNs enhanced cognitive function, alleviated oxidative stress, and improved the sleep quality of mice with high-altitude sleep disorders. The blockage of calcium ion overloading may be an important modulation mechanism. NDMNs are a promising and user-friendly formulation for the prevention of high-altitude sleep disorders. [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]

Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD. [ABSTRACT FROM AUTHOR]

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

Trazodone is a serotonin antagonist/reuptake inhibitor, approved for treating major depressive disorder (MDD). Oral formulations are widely studied and marketed in several countries worldwide while there is little evidence to support use of parenteral formulation. Our narrative review summarizes pharmacological properties and clinical data concerning use of parenteral trazodone in mood disorders. PubMed and Web of Science were used to identify the most relevant literature. The main evidence concerns four studies evaluating efficacy in major depressive disorder and indicates that trazodone was well tolerated and effective. Off-label use in agitation associated with bipolar disorder is also reported in three studies, although prescription of concomitant treatment, as a confounding factor, may have influenced outcome measures. The limited available evidence supports parenteral trazodone use in major depressive disorder and suggests that trazodone is a suitable option in patients at high risk of treatment-emergent mania (TEM). [ABSTRACT FROM AUTHOR]

Psychotropic drugs (PDs) include anxiolytics, sedatives and hypnotics, antidepressants, and antipsychotics, and they are available as medicines with different safety profiles. Given Portugal's high anxiolytic consumption and the rising prevalence of mental disorders, safety monitoring is crucial. This study aimed to analyze the individual case safety reports (ICSR) of suspected adverse drug reactions (ADRs) related to PDs, obtained through spontaneous reporting, and recorded in the Portuguese National Pharmacovigilance System between January 2017 and December 2021. This observational and retrospective study analyzed the ICSRs of suspected ADRs to PDs. Most reports pertained to female individuals (67.78%) between 18 and 64 years of age (63.71%). The pharmaceutical industry was the primary source of these reports (62.16%). Antidepressants were responsible for most ICSRs (61.90%). At least one serious ADR was recorded in 58.44% of the reports, and 43.84% of ADRs evolved into "cure". The most-observed ADRs were nausea (10.92%), dizziness (10.70%), and off-label use (10.30%). In the causality assessment, 45.49% of ADRs were classified as "possible", and only 4.96% were classified as "definitive". The current analysis helps to strengthen the safety evidence for PDs. In the future, some measures could be implemented to improve the use of and/or access to PDs, as well as to reinforce the rate of suspected ADR reports within the community, contributing to the safety data available. [ABSTRACT FROM AUTHOR]

Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography with photodiode array (UPLC-PDA) UV detection method was developed here for the first time for simple, rapid, selective and sensitive quantification of the commonly prescribed selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib in low plasma volumes (50 μL). The method includes protein precipitation followed by liquid–liquid extraction, evaporation and reconstitution. A gradient mobile phase of 75:25 going to 55:45 (v/v) water:acetonitrile (1 mL/min flow rate) was applied. Total run time was 8 min, representing a significant improvement relative to previous reports. Excellent linearity (r2 = 1) was obtained over a wide (0.1–12 µg/mL) etoricoxib concentration range. Short retention times for etoricoxib (4.9 min) and the internal standard trazodone (6.4 min), as well as high stability, recovery, accuracy, precision and reproducibility, and low etoricoxib LOD (20 ng/mL) and LOQ (100 ng/mL), were achieved. Finally, the method was successfully applied to a pharmacokinetic study (single 20 mg/kg orally administered etoricoxib mini-capsule) in rats. In conclusion, the advantages demonstrated in this work make this analytical method both time- and cost-efficient for drug monitoring in pre-clinical/clinical settings. [ABSTRACT FROM AUTHOR]

Insomnia is a frequent problem in adults and can become chronic. The burden of insomnia is significant so it should be identified and treated. [ABSTRACT FROM AUTHOR]

Abstract 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.

Trazodone is one of the most commonly used prescription medications for insomnia; however, some recent clinical guidelines do not recommend its use for treating insomnia. This clinical appraisal critically reviews the scientific literature on trazodone as a first-line treatment for insomnia, with the focus statement "Trazodone should never be used as a first-line medication for insomnia." In addition, field surveys were sent to practicing physicians, psychiatrists, and sleep specialists to assess general support for this statement. Subsequently, a meeting with a seven-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This paper reports on the evidence review, the panel discussion, and the panel's and healthcare professionals' ratings of the statement's acceptability. While the majority of field survey responders disagreed with the statement, the majority of panel members agreed with the statement based on the limited published evidence supporting trazodone as a first-line agent as they understood the term "first-line agent".

STUDY OBJECTIVES: To test the hypothesis that children taking trazodone have less leg movements during sleep (LMS) and higher rapid eye movement (REM) sleep atonia than children taking selective serotonin reuptake inhibitors (SSRIs) but more than normal controls. METHODS: Fifteen children (9 girls and 6 boys, mean age 11.7 years, standard deviation [SD] 3.42) taking trazodone (median dosage 50 mg/d, range 25-200 mg) for insomnia and 19 children (11 girls and 8 boys, mean age 13.7 years, SD 3.07) taking SSRIs for depression, anxiety, or both were consecutively recruited, as well as an age- and sex-matched group of 25 control children (17 girls and 8 boys, mean age 13.7 years, SD 3.11). LMS were scored and a series of parameters was calculated, along with the analysis of their time structure. The Atonia Index was then computed for each non-REM sleep stage and for REM sleep. RESULTS: Children taking trazodone exhibited slightly higher leg movement indices than controls but lower than those found in children taking SSRIs and their time structure was different. Chin electromyogram atonia in all sleep stages was not significantly altered in children taking trazodone but was decreased in children taking SSRIs, especially during non-REM sleep. CONCLUSIONS: In children, SSRIs but not trazodone are associated with a significantly increased number of LMS, including periodic LMS, and increased chin tone in all sleep stages. The assessment of periodic limb movement disorder and REM sleep without atonia might not be accurate when children are taking SSRIs because of their significant impact. CITATION: DelRosso LM, Mogavero MP, Bruni O, Schenck CH, Fickenscher A, Ferri R. Trazodone affects periodic leg movements and chin muscle tone during sleep less than selective serotonin reuptake inhibitor antidepressants in children. J Clin Sleep Med. 2022;18(12):2829-2836.

This is a case report of three cases of trazodone-induced buccal–lingual dyskinesias. Each case demonstrated the distinct pattern of the development of this dyskinesia after trazodone exposure for several months. All cases showed abrupt cessation of the movement disorder when the drug was discontinued. One of the three cases demonstrated a highly unusual presentation of an on/off pattern of buccal dyskinesia directly related to repetitive exposure and termination of the drug trazodone. Two of the three cases had no prior exposure to any dopamine blocking agents. One of the three had a distant exposure to a dopamine antagonist. As opposed to other antidepressants, trazodone has a mechanism of action which can account for both the development and treatment of dyskinetic movements. Its metabolite, M/chlorophenylpiperazine (M-CPP) is a 5HT2C agonist capable of causing abnormal oral-facial movements in rodent models. The presence of oromandibular dyskinetic movements can occur spontaneously with age, with trazodone being a potential predisposing factor. This article will discuss proposed mechanisms for trazodone's action with an emphasis on case reports of dystonic movements. [ABSTRACT FROM AUTHOR]

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. [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: Primary Stabbing Headache (PSH) is characterized by brief, focal, and paroxysmal pain ("stab"), occurring sporadically or in clusters. Data on pediatric cases are poor. Methods: We performed a comprehensive literature review by searching PubMed, Cochrane, and Embase in order to collect pediatric case reports and case series of PSH. Results: A total of 12 out of 162 articles assessed for eligibility were finally included. The prevalence of PSH and probable PSH varies from 2.5 to 10% among children with primary headaches and it is higher among children aged less than 6 years old. The mean age of onset is between 7 and 11 years of age. Attack duration greatly varies, ranging from a few seconds to several minutes. The intensity of pain is usually from moderate to severe. Associated symptoms are infrequent but may be observed (mainly photophobia, vertigo, nausea, and vomiting). Neuroradiological findings are usually unremarkable; EEG may show sporadic epileptiform abnormalities (up to 30% of cases). Preventive therapy is anecdotal, including treatment with indomethacin, trazodone, valproate, and amitriptyline. Conclusion: PSH is a common but still underdiagnosed entity among children with primary headaches; further and larger cohort studies are needed to better assess, in particular, prognosis and response to therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The behavioural variant of Frontotemporal Dementia (bvFTD) is a neurodegenerative condition characterized by behavioural and cognitive symptoms. Mood disturbances, including manic-like episodes, can occur in bvFTD, posing diagnostic and therapeutic challenges. This case report presents a 62-year-old male with bvFTD exhibiting weekly mood fluctuations alternating between manic and depressive-like states. While initial treatment with quetiapine and trazodone showed partial improvement, the periodicity of mood fluctuations persisted. Subsequently, lithium was introduced, resulting in a notable reduction in symptom severity for both manic and depressive episodes. This report highlights the potential use of lithium as a mood stabilizer in bvFTD patients with periodic mood fluctuations, refractory to standard treatments. Further research is needed to elucidate the mechanisms underlying lithium's efficacy in bvFTD and to establish treatment guidelines. [ABSTRACT FROM AUTHOR]

Transdermal drug delivery is of vital importance for medical treatments. However, user adherence to long-term repetitive drug delivery poses a grand challenge. Furthermore, the dynamic and unpredictable disease progression demands a pharmaceutical treatment that can be actively controlled in real-time to ensure medical precision and personalization. Here, we report a spatiotemporal on-demand patch (SOP) that integrates drug-loaded microneedles with biocompatible metallic membranes to enable electrically triggered active control of drug release. Precise control of drug release to targeted locations (<1 mm2), rapid drug release response to electrical triggers (<30 s), and multi-modal operation involving both drug release and electrical stimulation highlight the novelty. Solution-based fabrication ensures high customizability and scalability to tailor the SOP for various pharmaceutical needs. The wireless-powered and digital-controlled SOP demonstrates great promise in achieving full automation of drug delivery, improving user adherence while ensuring medical precision. Based on these characteristics, we utilized SOPs in sleep studies. We revealed that programmed release of exogenous melatonin from SOPs improve sleep of mice, indicating potential values for basic research and clinical treatments. Microneedle patches that can actively address individual needles are challenging to realize. Here, the authors introduce a spatiotemporal on-demand patch for precise and personalized drug delivery, utilizing electrically triggered control with drug-loaded microneedles and biocompatible metallic membranes. [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]

we aimed to compare the effects of atomoxetine and trazodone (A-T) in combination with placebo in patients with obstructive sleep apnea (OSA). 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. 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. 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. • Obstructive sleep apnea severity decreased significantly after the administration of Atomoxetine and Trazodone. • Respiratory and hypoxia indices improved with pharmacological intervention. • Apnea hypopnea index decreased after administration of Atomoxetine and Trazodone combination. • Pharmacologic treatment could be a good alternative for patients with low adherence or no access to standard OSA management. [ABSTRACT FROM AUTHOR]