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.

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.

ANTIDEPRESSANT MEDICATIONS ARE ASSOCIATED WITH INCREASED RISK OF HOSPITAL-ACQUIRED CLOSTRIDIOIDES DIFFICILE INFECTION: A POPULATION-BASED STUDY.

WHAT IS ALREADY KNOWN: •The rate and severity of Clostridioides difficile infection (CDI) has increased throughout North America, the United Kingdom, and Europe. •Scattered evidence about the association of CDI with antidepressant medications use exists in the literature so far. What are the new findings: •The risk of Clostridioides difficile infection is higher in patients who are on mirtazapine, nortriptyline, or trazodone. •The prevalence rate of Clostridioides difficile infection in patients who were using antidepressant medications and the ones who did not, increased with age. Background - During the past decade, Clostridioides difficile infection (CDI) has become the most common cause of antibiotic-associated diarrhea. Several risk factors have been implicated. Scattered evidence about the association of CDI with antidepressant medications use exists in the literature so far. Therefore, we aim to investigate whether the risk of developing CDI is increased in hospitalized patients using antidepressant medications.Methods - Patients who were hospitalized were included in our cohort. We excluded individuals aged less than 18 years. A multivariate regression analysis was performed to calculate the risk of CDI accounting for potential confounders. Results - The risk of CDI in hospitalized patients was increased in individuals diagnosed with inflammatory bowel disease (OR: 4.44; 95%CI: 4.35-4.52), and in patients using clindamycin (OR: 1.55; 95%CI: 1.53-1.57), beta-lactam antibiotics (OR: 1.62; 95%CI: 1.60-1.64), PPI (OR: 3.27; 95%CI: 3.23-3.30), trazodone (OR: 1.31; 95%CI: 1.29-1.33), nortriptyline (OR: 1.25; 95%CI: 1.21-1.28), and mirtazapine (OR: 2.50; 95%CI: 2.46-2.54). After controlling for covariates, the risk of CDI was not increased in patients who were taking fluoxetine (OR: 0.94; 95%CI: 0.92-0.96). Conclusion - In contrary to fluoxetine; mirtazapine, nortriptyline, and trazodone were associated with increased risk of CDI in hospitalized patients.

Successful treatment of auto-trilevel positive airway pressure plus trazodone for obstructive sleep apnea complicated by anxiety disorder: a case report.

Obstructive sleep apnea (OSA) is a highly prevalent type of sleep-disordered breathing, which is often comorbid with affective disorders such as anxiety. A 61-year-old woman who was diagnosed with OSA affected by anxiety disorder complained of poor sleep quality at night and anxiety symptoms, and showed chest tightness, dyspnea, snoring, and apnea events during sleep. The patient initially received treatment with positive airway pressure (PAP) combined with trazodone, and subsequently switched to auto-trilevel PAP (AtPAP) combined with trazodone therapy. The initial attempt to treat the patient's disease by auto-adjusting PAP combined with trazodone failed because of central sleep apnea (CSA), which frequently occurred at night. After switching to AtPAP combined with trazodone therapy, CSA was effectively eliminated. In addition, sleep quality, hypoxia, and anxiety disorders were improved. The first report of successful therapy of AtPAP combined with trazodone for OSA complicated by anxiety disorder provides a new therapeutic strategy for this patient population.

Trazodone for sleep disturbance in opioid dependent patients maintained on buprenorphine: A double blind, placebo-controlled trial.

BACKGROUND: Sleep disturbances are seen even in individuals on opioid agonist treatment (OAT). Established pharmacotherapy for sleep disturbances such as benzodiazepines have misuse potential and increased mortality risk in patients with OAT. No study has explored the role of trazodone on sleep disturbance in individuals maintained on buprenorphine. We aimed to assess the efficacy of trazodone in improving sleep disturbance among individuals maintained on buprenorphine. METHODS: The study was a double-blind, placebo-controlled, parallel, randomised trial. Adult males (18-60 years) stabilised on buprenorphine with Pittsburgh Sleep Quality Index (PSQI) score of above five, without other psychiatric comorbidity were randomised to receive either trazodone (50-150mg per day) or placebo. Sleep-50 questionnaire, Epworth Sleepiness Scale (ESS), Brief Pain Inventory (BPI), Clinical Opiate Withdrawal Scale (COWS), Depression, Anxiety and Stress Scale (DASS)-21, Visual Analogue Scale (VAS) for opioid craving, and PSQI were assessed at baseline and at the end of six weeks. RESULTS: Fifty-one patients were allocated to trazodone arm and 49 to placebo arm. Side-effects of trazodone were minimal and well-tolerated with comparable discontiuation rates between both groups. Significantly greater proportion of patients on trazodone (82%, mean dose 101.9 mg) had PSQI scores five or less than those on placebo (16%) at the end of six weeks. Sleep improvement was in various components like sleep quality, latency, efficiency, and duration of sleep. CONCLUSION: Trazodone is well-tolerated and effective in improving sleep disturbances in individuals with opioid dependence maintained on buprenorphine over a six-week period.

[Treatment of mental disorders caused or triggered by somatic and neurological diseases with the use of the multimodal antidepressant trazodone]. / Terapiya psikhicheskikh rasstroistv, obuslovlennykh libo provotsirovannykh somaticheskoi i nevrologicheskoi patologiei, s primeneniem mul'timodal'nogo antidepressanta trazodon.

The purpose of this narrative review is to relate current data on the molecular mechanisms of action of trazodone with its clinical effects and applicability in mental disorders caused or triggered by somatic and neurological disease, according to available publications. In the article, the prospects for the use of the multimodal antidepressant trazodone are discussed in accordance with therapeutic targets. The latter are discussed in accordance with the typology of the mentioned above psychosomatic disorders. Trazodone is an antidepressant acting primarily due to the blockade of postsynaptic serotonin 5H2A- and 5H2C-receptors, as well as the blockade of serotonin reuptake, but also has affinity for a number of additional receptors. The drug has a favorable safety profile and a wide range of beneficial effects: antidepressive, somnolent, anxiolytic, anti-dysphoric and somatotropic. This makes it possible to influence a wide range of therapeutic targets in the structure of mental disorders caused or triggered by somatic and neurological diseases, carrying out safe and effective psychopharmacotherapy.

Investigating the effectiveness of electronically delivered cognitive behavioural therapy (e-CBTi) compared to pharmaceutical interventions in treating insomnia: Protocol for a randomized controlled trial.

BACKGROUND: Insomnia is one of the most prevalent sleep disorders characterized by an inability to fall or stay asleep. Available treatments include pharmacotherapy and cognitive behavioural therapy for insomnia (CBTi). Although CBTi is the first-line treatment, it has limited availability. Therapist-guided electronic delivery of CBT for insomnia (e-CBTi) offers scalable solutions to enhance access to CBTi. While e-CBTi produces comparable outcomes to in-person CBTi, there is a lack of comparison to active pharmacotherapies. Therefore, direct comparisons between e-CBTi and trazodone, one of the most frequently prescribed medications for insomnia, is essential in establishing the effectiveness of this novel digital therapy in the health care system. OBJECTIVE: The aim of this study is to compare the effectiveness of a therapist-guided electronically-delivered cognitive behavioural therapy (e-CBTi) program to trazodone in patients with insomnia. METHODS: Patients (n = 60) will be randomly assigned to two groups: treatment as usual (TAU) + trazodone and TAU + e-CBTi for seven weeks. Each weekly sleep module will be delivered through the Online Psychotherapy Tool (OPTT), a secure, online mental health care delivery platform. Changes in insomnia symptoms will be evaluated throughout the study using clinically validated symptomatology questionnaires, Fitbits, and other behavioural variables. RESULTS: Participant recruitment began in November 2021. To date, 18 participants have been recruited. Data collection is expected to conclude by December 2022 and analyses are expected to be completed by January 2023. CONCLUSIONS: This comparative study will improve our understanding of the efficacy of therapist-guided e-CBTi in managing insomnia. These findings can be used to develop more accessible and effective treatment options and influence clinical practices for insomnia to further expand mental health care capacity in this population. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05125146).

[Pimavanserin and trazodone combination in behavioral disorders in severe dementia with Lewy bodies]. / Association pimavansérine et trazodone dans les troubles du comportementde la maladie à corps de Lewy sévère.

INTRODUCTION: Dementia with Lewy bodies (DLB) is characterized by neurocognitive disorders associated with core clinical features including hallucinations. There is currently no cure but a combination of symptomatic treatments: clozapine is commonly used in DLB-related psychosis. Pimavanserin is a serotonin 5HT-2A receptor inverse agonist that has recently been shown to reduce psychosis related to dementia. Trazodone is a serotonin reuptake inhibitor and a 5-HT2 receptor antagonist: it is effective in the treatment of the frontal syndrome and is commonly used in frontotemporal degeneration. PATIENTS AND METHODS: We describe three patients with DLB, hospitalized in the cognitive-behavioral unit of the University Hospitals of Strasbourg, who presented with major visual hallucinations, delusion, and an orbitofrontal syndrome including disinhibition, agitation, and irritability. The 3 patients were intolerant of low-dose Clozapine (neutropenia for one, somnolence for the other and Pisa syndrome and falls for the last one). We evaluated the Neuropsychiatric Inventory (NPI) before and after the introduction of both treatments. RESULTS: Given their psychotic and frontal symptoms, we used Pimavanserin and Trazodone simultaneously. After 4 to 6 weeks of treatment, a marked improvement was observed in all 3 patients, with a decrease of the NPI scores from a mean of 88 to 38. DISCUSSION AND CONCLUSION: To our knowledge, there is no previously described combination of these two treatments in DLB. A clinical trial combining these two molecules against pervasive behavioral disorders in DLB would be interesting in view of these preliminary results.

Update on Pharmacological Treatment for Comorbid Major Depressive and Alcohol Use Disorders: The Role of Extended-release Trazodone.

BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are major public health concerns because of their high prevalence and clinical and functional severity. MDD and AUD commonly co-occur, but effective therapeutic approaches for comorbidity are still scarce. Available evidence on selective serotonin reuptake inhibitors and tricyclic antidepressants held mixed results, and further pharmacological categories have been less investigated. Trazodone is an approved antidepressant drug for adults and has shown efficacy on symptoms like anxiety and insomnia observed in AUD patients as well. Thus, this study aims to evaluate the effect of extended-release trazodone on clinical and functional features in MDD + AUD subjects. METHODS: One hundred MDD + AUD outpatients were retrospectively evaluated at 1, 3, and 6 months of treatment with extended-release trazodone (150-300 mg/day, flexibly dosed). Improvement in depressive symptoms was the primary outcome measure. Changes in anxiety, sleep, functioning, quality of life, clinical global severity, and alcohol craving were also investigated. RESULTS: Trazodone reduced depressive symptoms (p < 0.001) with 54.5% remission at the endpoint. Similar improvements were observed in all secondary outcomes, including anxiety, sleep alterations, and craving (p < 0.001). Only mild side effects were reported and disappeared over time. CONCLUSION: Extended-release trazodone displayed good antidepressant properties in MDD + AUD patients, ameliorating overall symptomatology, functioning, and quality of life, with a good safety/ tolerability profile. Further, it significantly improved sleep disturbances and craving symptoms, which are associated with drinking relapse and worse outcomes. Therefore, trazodone might represent a promising pharmacological option for MDD + AUD patients.

Comparison of the efficacy of Trazodone hydrochloride tablets alone and in combination with press-needles in the treatment of post-stroke depression.

The purpose of this study was to compare the efficacy of Trazodone hydrochloride tablets alone and in combination with press-needles in the treatment of post-stroke depression. One hundred and four post-stroke depression patients, admitted to Yantaishan Hospital, China, from August 2019 to June 2021, were randomly divided in two groups: Group A (n=52) and Group B (n=52). Group A was given oral Trazodone hydrochloride tablets, while Group B was treated with press-needle and Trazodone hydrochloride tablets. Post treatment assessment revealed that after treatment, National Institutes of Health Stroke Scale scores, Hamilton Depression Rating Scale scores, serum 5-hydroxytryptamine and brain-derived neurotrophic factor levels of Group B were lower than those of Group A (all p<0.001). Treatment efficiency of Group B was higher than that of Group A (p=0.014). Compared with Trazodone hydrochloride tablets alone, Trazodone hydrochloride tablets combined with press-needles may reduce neurological impairment and depressive mood in post-stroke depression patients more effectively. It can be because the combination better promotes the increase of 5-hydroxytryptamine and brain-derived neurotrophic factor.

Attempting to Increase the Effectiveness of the Antidepressant Trazodone Hydrochloride Drug Using π-Acceptors.

Major depressive disorder is a prevalent mood illness that is mildly heritable. Cases with the highest familial risk had recurrence and onset at a young age. Trazodone hydrochloride is an antidepressant medicine that affects the chemical messengers in the brain known as neurotransmitters, which include acetylcholine, norepinephrine, dopamine, and serotonin. In the present research, in solid and liquid phases, the 1:1 charge-transfer complexes between trazodone hydrochloride (TZD) and six different π-acceptors were synthesized and investigated using different microscopic techniques. The relation of dative ion pairs [TZD+, A-], where A is the acceptor, was inferred via intermolecular charge-transfer complexes. Additionally, a molecular docking examination was utilized to compare the interactions of protein receptors (serotonin-6BQH) with the TZD alone or in combination with the six distinct acceptor charge-transfer complexes. To refine the docking results acquired from AutoDock Vina and to better examine the molecular mechanisms of receptor-ligand interactions, a 100 ns run of molecular dynamics simulation was used. All the results obtained in this study prove that the 2,6-dichloroquinone-4-chloroimide (DCQ)/TZD complex interacts with serotonin receptors more efficiently than reactant donor TZD only and that [(TZD)(DCQ)]-serotonin has the highest binding energy value of all π-acceptor complexes.

Effects of trazodone administration on the neurologic examination in healthy dogs.

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.

Thyrotropin-releasing hormone analog as a stable upper airway-preferring respiratory stimulant with arousal properties.

Taltirelin is a stable, brain-penetrating thyrotropin-releasing hormone (TRH) analog with minimal endocrine activity and potential respiratory stimulant properties. Taltirelin's receptor target shows high differential expression at the hypoglossal motor nucleus, and local taltirelin microperfusion into the hypoglossal motor nucleus causes sustained tongue motor activation compared with the transient activating effects of TRH itself. Here, we performed a randomized, within-subject, repeated-measures design over six separate study days (separated by at least 72 h) in chronically instrumented male (n = 10) and female (n = 9) rats to identify effects on sleep and breathing. Vehicle controls or taltirelin (0.1 and 1 mg/kg) with and without trazodone (30 mg/kg) were administered by intraperitoneal injection. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. Systemically administered taltirelin (1 but not 0.1 mg/kg) increased tonic and within-breath phasic tonic muscle activity compared with vehicle controls (P ≤ 0.007), with little or no changes in diaphragm amplitude or respiratory rate. Taltirelin also suppressed nonrapid eye movement (non-REM) sleep and increased wakefulness (P ≤ 0.037). Other indices of taltirelin-induced central nervous system arousal included increased trapezius muscle tone in non-REM sleep and decreased total electroencephalogram power and δ (0.5-4 Hz) power (P ≤ 0.046). These effects were especially apparent in non-REM sleep and not prevented by trazodone. These preclinical findings identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties, traits that have potential favorable relevance to some respiratory disorders but not others.NEW & NOTEWORTHY One of the major goals for translational sleep science and medicine is to identify viable and tractable pharmacological targets for obstructive sleep apnea and other respiratory disorders of sleep or sedation. In the present preclinical study in rats, we performed a randomized, within-subject, repeated-measures design over six intervention study days in chronically instrumented male and female rats with systemic peripheral administration of vehicle controls, the thyrotropin-releasing hormone analog taltirelin at two doses, all with and without coadministered trazodone. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. These preclinical findings newly identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties. These traits have potential favorable relevance to some respiratory disorders but not others, as identified and discussed.

Trazodone and patient outcomes in dementia-Limitations of naturalistic cohort data.

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.

Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis.

Trazodone has been widely prescribed for off-label use as a sleep aid. Identifying how trazodone impacts the performance of polysomnographic sleep architecture in insomnia disorder will provide additional data that can be used to guide clinical application. To assess the efficacy of trazodone in altering the polysomnographic sleep architecture in insomnia disorder so that sleep can be facilitated. PubMed, EMBASE, Web of Science, PsycINFO, Cochrane Library, Chinese Biomedical Literature Database (SinoMed), China National Knowledge Infrastructure, Wanfang Database, and the China Science and Technology Journal Database were searched for articles published between inception and June 2022. RCTs in patients with insomnia disorder applying trazodone in one arm of interventions at least 1 week, and reporting PSG parameters in the outcomes were eligible. RoB 2 was used to evaluate the risk of bias. The results of quality of evidence assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. When I2 < 50%, the fixed effects model was used. When I2 ≥ 50%, the random effects model was used. The mean differences (MD) or standardized mean differences (SMD) and odds ratios (OR) with 95% confidence intervals (CIs) were estimated. Eleven randomized controlled trials were selected and participants were 466. Risk of bias was low in 5 trials (45.5%), and was moderate in 6 (54.5%). Compared with the control group, trazodone significantly increased total sleep time (TST, min) (MD = 39.88, 95% CI 14.44-65.32, P = 0.002) and non-rapid eye movement stage 3 (N3, mixed min and %) (SMD = 1.61, 95% CI 0.69-2.53, P = 0.0006); trazodone significantly decreased latency to onset of persistent sleep (LPS, min) (MD = - 19.30, 95% CI - 37.28 to - 1.32, P = 0.04), non-rapid eye movement stage 1 (N1, mixed min and %) (SMD = - 0.62, 95% CI - 1.13 to - 0.12, P = 0.02), the number of awakenings (NAs, including both arousal times and arousal index) (SMD = - 0.67, 95% CI - 0.91 to - 0.42, P < 0.00001), and waking time after persistent sleep onset (WASO, mixed min and %) (SMD = - 0.42, 95% CI - 0.81, - 0.03, P = 0.04), with no obvious effect on non-rapid eye movement stage 2 (N2, mixed min and %) (SMD = - 0.15, 95% CI - 0.41 to 0.11, P = 0.25), rapid eye movement (REM, mixed min and %) (SMD = 0.22, 95% CI - 0.26 to 0.70, P = 0.37), rapid eye movement latency (REML, min) (MD = 2.33, 95% CI - 27.56 to 32.22, P = 0.88), or apnea-hypopnea index (AHI) (MD = - 4.21, 95% CI - 14.02 to 5.59, P = 0.40). Daytime drowsiness (OR = 2.53, 95% CI 1.14-5.64, P = 0.02) and decreased appetite (OR = 2.81, 95% CI 1.14-6.92, P = 0.02) occurred with greater frequency in the trazodone group as compared to the control group, and the differences were significant. The results of quality of evidence were very low in TST, N3 and AHI, were low in LPS, WASO and REM, and were moderate in N1 and NAs. The sources of heterogeneity in TST and N3 were not found out from sensitive and subgroup analysis and there was no high quality of evidence in outcomes by GRADE Assessment. Trials with combination of other therapy could be a problem in this meta-analysis as the possibility of interactions were found from sungroup analysis. Trazodone could improve sleep by changing the sleep architecture in insomnia disorder, but it should be used with caution due to the adverse events that may occur.PROSPERO registration register name: The effect of trazodone on polysomnography sleep architecture in patients with insomnia: a systematic review and meta-analysis protocol; Registration Number CRD42020215332.

Real-World Characteristics and Treatment Patterns of Patients With Insomnia Prescribed Trazodone in the United States.

PURPOSE: This study sought to describe patient characteristics and treatment patterns among patients with insomnia prescribed trazodone in the United States. METHODS: This real-world, retrospective, descriptive cohort study used US commercial insurance claims from July 1, 2009, through June 30, 2019. The index date was the first prescription for trazodone between January 1, 2010, and December 31, 2018, with 6 months for the preindex period and ≥6 months for the postindex period. FINDINGS: Among 5.8 million patients with insomnia, 17.7% were prescribed trazodone, and 357,380 adults (6.2%) and 7564 children (0.1%) met the study eligibility criteria. The mean (SD) age was 48.8 (15.8) years for adults and 14.8 (2.7) years for pediatrics. Most patients were female (229,280 adults [64.2%] and 4481 children [59.2%]). Insomnia due to mental disorder was the most common specific diagnosis. The most common (>25%) comorbid conditions were anxiety, depression, and hypertensive disease, and 1 of 10 had a history of substance abuse. Zolpidem was previously prescribed (73,342 adults [20.5%] and 233 children [3.1%]) and continued to be prescribed. Concomitant antidepressants were most common (216,893 adults [60.7%] and 5414 children [71.6%]), but benzodiazepines (132,740 adults [37.1%] and 1188 children [15.7%]), antiepileptics (115,064 adults [32.2%] and 2103 children [27.8%]), nonbenzodiazepines (90,946 adults [25.4%] and 542 children [7.2%]), and antipsychotics (40,490 adults [11.3%] and 2063 children [27.3%]) were also prescribed. IMPLICATIONS: This study provides current evidence that trazodone use is widespread among patients with insomnia and is often associated with other specific comorbidities, such as psychiatric conditions. A deeper knowledge of the real-world management of patients with insomnia may facilitate steps toward improving sleep quality, daytime functioning, and clinical outcomes for patients.

Influence of trazodone on the pharmacodynamics and pharmacokinetics of pioglitazone.

BACKGROUND: These days, poly pharmacy is very common for the treatment of multiple diseases and majority of drugs were metabolized with CYP 450 enzymes. Diabetes mellitus is such a disorder, which requires continuous therapy for the control of blood glucose concentration. Depression was quite common in diabetic patients. Therefore, multiple drugs required to treat diabetes mellitus and depression. Simultaneous administration of these drugs leads to drug interaction. Pioglitazone and trazodone metabolized by CYP3A4 enzymes which may lead to potential drug interaction. OBJECTIVES: This study aimed to find the influence of trazodone on the pharmacokinetics & pharmacodynamics of pioglitazone in normal & diabetic rats, also on rabbits and subsequently effectiveness and safety of the combination was evaluated. METHODS AND MATERIAL: Blood glucose concentration was determined by Glucose oxidase/peroxidase method in normal and diabetic rats. Diabetes was induced with Streptozotocin at a dose of 55 mg/kg body weight. Serum pioglitazone concentration was estimated by high performance liquid chromatography method for pharmacokinetic data. The values were expressed as Mean ± Standard Error Mean (SEM), GraphPad Prism 3.0 (San Diego, California, USA) software was used to express the data. Student's paired 't' test was used to determine the significance. RESULTS: Pioglitazone produces hypoglycaemia in normal rats with a maximum decrease of 36.78 % ± 0.81 at 3 hours interval and anti-hyperglycaemic activity in diabetic rats with maximum reduction of 45.13 % ± 1.52 at 2 hours interval. Trazodone altered the pharmacokinetics of pioglitazone and improved the pioglitazone hypoglycaemic effect. CONCLUSION: Trazodone apparently produced pharmacokinetic interaction with pioglitazone which might be by attenuating the metabolism of pioglitazone. Therefore, care should be taken in simultaneous therapy with pioglitazone and trazodone.

Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease.

INTRODUCTION: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine. METHODS AND ANALYSIS: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments. ETHICS AND DISSEMINATION: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants. TRIAL REGISTRATION NUMBERS: European Clinical Trials Registry (2019-000099-41); NCT04302870.

Trazodone Prolonged-Release Monotherapy in Cannabis Dependent Patients during Lockdown Due to COVID-19 Pandemic: A Case Series.

(1) Background: During the SARS-CoV-2 (COVID-19) pandemic, cannabis use increased relative to pre-pandemic levels, while forced home confinement frequently caused sleep/wake cycle disruptions, psychological distress, and maladaptive coping strategies with the consequent appearance of anxiety symptoms and their potential impact on substance use problems. (2) Aim: Long-acting trazodone (150 mg or 300 mg daily) has a potential benefit as monotherapy in patients with cannabis use disorder. The present work aims to investigate the effectiveness of trazodone in optimizing the condition of people with cannabis dependence under pandemic conditions. (3) Methods: All cases with cannabis use disorder were uniformly treated with long-acting trazodone 150 mg or 300 mg/day; their craving and clinical status were monitored through appropriate psychometric scales. Side effects were recorded as they were reported by patients. We described the cases of three young patients-one man and two women-who were affected by chronic cannabis use disorder and who experienced lockdown-related psychological distress and sought psychiatric help. (4) Results: The described cases highlight that the once-a-day formulation of trazodone seems to have a therapeutic role in patients with cannabis use disorder and to guarantee tolerability and efficacy over time. No significant side effects emerged. (5) Conclusions: The use of long-acting trazodone (150 mg or 300 mg daily) has a potential benefit as monotherapy in patients with cannabis use disorder. Trazodone deserves to be studied in terms of its efficacy for cannabis use disorder.