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Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

The review of the literature contains data on neuropsychiatric (non-cognitive) symptoms in various types of dementia, which are quite heterogeneous and in most cases unpredictable, affect the emotional sphere, perception and motor function of patients. Typical behavioral disorders associated with certain types of dementia are described. It is recommended to combine non-pharmacological interventions with pharmacotherapy for patients with all types and different degrees of severity of dementia with concomitant non-cognitive symptoms. The therapeutic possibilities of various groups of drugs used for the treatment of behavioral disorders in dementia (cholinesterase inhibitors, NMDA receptors, anticonvulsants, antidepressants) were described in this review. According to current recommendations, the use of atypical antipsychotics should be avoided or, if necessary, minimized. From the position of evidence-based medicine, taking into account data of numerous clinical trials, there was found a significant efficacy of antidepressant with multimodal properties — trazodone in the treatment of behavioral disorders in dementia (irritability, agitation, anxiety, depressive disorders, insomnia and eating behavioral disorders).

The article deals with the various types of vertebrogenic and musculoskeletal pain syndromes. Special attention is paid to the place of structure-modifying agents in the complex of treatment for chronic pain syndrome in these patients, as well as the impact on the psychological components of pain syndrome, including depression and anxiety., Статья посвящена различным видам вертеброгенных и мышечно-скелетных болевых синдромов. Особое внимание уделяется месту структурно-модифицирующих препаратов в комплексе лечения хронического болевого синдрома у данной категории больных, а также воздействию на психологические компоненты болевого синдрома, включая депрессию и тревогу., Стаття присвячена різним видам вертеброгенних і м’язово-скелетних больових синдромів. Особлива увага приділяється місцю структурно-модифікуючих препаратів у комплексі лікування хронічного больового синдрому в даної категорії хворих, а також впливу на психологічні компоненти больового синдрому, включаючи депресію і тривогу.

COVID-19 represents a significant stress factor for all people worldwide due to several factors, including quarantine, lockdowns, fear of contagion, deaths, and other traumatic events. However, the healthcare workers (HCWs) have paid the higher price of this pandemic in terms of fatalities, contagions, and psychological well-being. Studies suggest that this particular population is at increased risk of developing a severe post-traumatic stress disorder (PTSD). The early diagnosis and timely treatment of PTSD in HCWs may restore well-being and significantly impact health services functioning, reducing burnout, days spent far from work, disrupted personal and team empowerment, and worse job performances. In the present article, we reported on two cases of HCWs directly involved in the treatment of COVID-19 patients who showed selective serotonin reuptake inhibitor-resistant PTSD, which was successfully treated with extended-release trazodone TRZ ContramidⓇ add-on.

Currently, the interest of veterinarians and owners in the pharmacological correction of situational behavioral disorders in companion animals has increased significantly. To quickly correct deviant behavior in dogs and cats, veterinarians use some of the psychotropic drugs used in humane medicine, in particular, trazodone, an antidepressant antagonist / serotonin reuptake inhibitor. Based on the analysis of literature sources, data on the history of creation and pharmacological properties, assessment of the safety and efficacy of drugs based on trazodone hydrochloride in behavioral medicine of small pets are provided. The data on the prerequisites for the development, pharmaco-toxicological and clinical evaluation of a new drug for the modification of abnormal behavior in dogs and cats, Express Uspokoin® tablets based on trazodone succinate, which, with a high efficiency of the target action, made it possible to achieve the absence of side effects and significantly increase the tolerance of the dosage form by animals, are analyzed. compared with preparations based on trazodone hydrochloride.

Background: Trazodone is used to treat anxiety disorder, insomnia, and sleep disorders, which occur in ∼15% of pregnant and lactating women. However, pharmacokinetic information on the transfer of trazodone and its active metabolite, 1-m-chlorophenylpiperazine (mCPP), across the placenta or into breast milk is limited. In this study, we describe the pharmacokinetic profile of trazodone and mCPP concentrations in maternal and neonatal blood and breast milk. Case Presentation: A 44-year-old female received oral trazodone 50 mg once daily during pregnancy (28–38 gestational weeks) and lactation, along with etizolam for anxiety disorder with depressive syndrome. A male infant weighing 2,918 g was born at 38 weeks of gestation. Because of persistent respiratory disturbance, oxygenation was initiated immediately after birth, and the infant was admitted in the neonatal intensive care unit for 5 days. No pulmonary dysfunction or birth defects were detected, and no medication and circulatory support were needed during admission. Trazodone and mCPP concentrations in cord blood at 7.4 hours after maternal dosing were 267.6 and 22.8 ng/mL, respectively, which were comparable with maternal serum levels. The trazodone and mCPP concentrations in breast milk collected 7.2 hours after maternal dosing were 50.2 and 3.2 ng/mL, respectively. The infant developed normally, with no drug-related adverse effects at the 1-, 3-, and 6-month postpartum checkups. Conclusion: Trazodone and its active metabolite were transferred into placenta and breast milk. However, their effects in utero could not be clarified. Further studies are warranted to assess the safety of trazodone in fetuses and breastfed infants.

Objectives To review medical malpractice trends and to identify the most common claims filed against medical providers for the management of patients with priapism. Methods Using the Westlaw legal database, a search was done for the keyword “priapism” between July 1, 1980 and July 1, 2020. Cases were evaluated for plaintiff demographics, reasons for filing claims, management outcomes, legal verdicts and awards and further categorized based upon the timing of the alleged malpractice. Results Alleged negligence during the pre-management period was cited in 30 cases. Administration of psychotropic medications was the most common reasons for filing pre-management claims 22/56 (39.3%). Delay in care accounted for 18/56 (32.1%) and complications of surgery were 5/56 (8.9%) of claims. The majority of the completed cases were in favor of the defendants (39/47; 83.0%). There was no association between type of health care provider or timing of alleged malpractice and ultimate verdict. Conclusions Prescribing psychoactive medications without warning of the adverse effect profile is the most common reason for claims filed against providers with trazodone as the leading medication. Medical providers should ensure that patients are well informed of this adverse effect prior to prescription. Regardless, the majority of medical malpractice cases carry a verdict in favor of the defendant.

Sedatywne leki przeciwdepresyjne są często stosowanymi lekami w leczeniu bezsenności. Cześć z zaleceń jako leki o udowodnionej skuteczności w leczeniu zaburzeń zasypiania i utrzymania snu wskazuje jednak głównie leki nasenne. Celem artykułu było porównanie wpływu na sen leków nasennych i trazodonu oraz analiza wskazań do stosowania trazodonu w leczeniu chorych zgłaszających się do lekarza z powodu bezsenności. Zidentyfikowano trzy badania oceniające wpływ trazodonu na sen w bezsenności, 5 badań w bezsenności w przebiegu zaburzeń afektywnych i 6 badań w innych wskazaniach (PTSD, choroba Alzheimera, uzależnienie od alkoholu i opiatów, zaburzenia pod postacią somatyczną, bezsenność w ciąży). W leczeniu bezsenności trazodon ustępuje lekom nasennym w sile i szybkości indukowania snu (zasypiania). W tym wskazaniu musi być podawany wcześniej niż leki nasenne, co najmniej 1 godzinę przed planowaną porą snu. Jest natomiast skuteczny w leczeniu zaburzeń utrzymania snu, szczególnie u chorych z współistniejącymi zaburzeniami psychicznymi lub leczonych aktywizującymi lekami przeciwdepresyjnymi. Leki nasenne i trazodon mają przeciwny efekt na sen głęboki. Trazodon zwiększa długość snu głębokiego, co powiązane jest z odczuwaniem przez pacjentów poprawy jakości snu. Natomiast leki nasenne zmniejszają aktywność fal wolnych w EEG snu, która jest biologicznym markerem głębokości snu. Głównym mechanizmem, w którym trazodon promuje sen jest silne antagonistyczne działanie na receptory serotoninowe 5-HT2, podczas gdy dla leków nasennych jest nim agonistyczne działanie na receptory kwasu gama-aminomasłowego GABAA, a innych sedatywnych leków przeciwdepresyjnych blokowanie receptorów histaminowych H1. Ten mechanizm działania związany jest z niskim ryzykiem przyrostu masy ciała, który rzadko jest obserwowany w trakcie leczenia trazodonem.

Serotonin discontinuation syndrome (SDS) can result in a constellation of symptoms exhibited by infants exposed to selective serotonin reuptake inhibitors or other psychotropic drugs during pregnancy. Currently, there is no consensus regarding the pharmacologic management of SDS. We report our experience with clonidine for the management of a term infant with poor neonatal adaption. The infant exhibited biphasic symptoms of acute toxicity at birth and a plateauing of symptoms, followed by subsequent withdrawal symptomatology requiring the use of clonidine in doses up to 4 mcg/kg/dose every 3 hours for control of symptoms. The 38-week gestation Caucasian male infant was born to a mother with major depressive disorder, which was managed with sertraline, trazodone, venlafaxine, and buspirone throughout her pregnancy. The infant exhibited severe hypertonia at delivery and continued to have hypertonia, tremors, hypoglycemia, and feeding issues upon admission to the NICU. The initial Modified Finnegan Neonatal Abstinence scores were extremely elevated, and clonidine was started at 1 mcg/kg/dose every 3 hours and then the dose was titrated up to 4 mcg/kg/dose. This is the first report documenting the use of clonidine to manage serotonin toxicity at birth followed by subsequent neonatal withdrawal associated with maternal antidepressant drug use during pregnancy.

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

Barre-Lieou syndrome (BLS) is a manifestation of various autonomic and secondary symptoms including muscle stiffness, tinnitus, dizziness, and pain in various body parts. Although considered to be caused by hyperactivation of the autonomic nervous system due to trauma, there is currently no firmly established etiology or evidence on the treatment and clinical features of BLS. We retrospectively examined the clinical features of BLS and evaluated the efficacy of trazodone (TZD) for its treatment. We conducted a retrospective analysis of the data of 20 consecutive cases with suspected BLS who were treated in our hospital between 2016 and 2019. BLS symptoms were rated on a 10-point scale, and two groups were defined, that is, a mild-BLS group (BLS scores, 1-5) and a severe-BLS group (BLS scores, 6-10). Univariate analysis of patient factors was performed. The BLS score was 6.0 ± 1.7, and the maximum TZD dose was 80 ± 34 mg/day; nine patients (45%) were TZD free, and no TZD side effects were observed, while all patients had a good clinical outcome. There were significant differences between the mild-BLS and severe-BLS groups in the period from injury to diagnosis (p = 0.015), chest/back pain (p < 0.001), constipation (p = 0.001), and maximum TZD dose (p = 0.008). BLS involves posttraumatic autonomic symptoms accompanied by depression and insomnia. The sympathetic hypersensitivity theory could explain its etiology. TZD could effectively and safely treat BLS, and early diagnosis and treatment can contribute toward good clinical outcomes. Enhanced recognition and understanding of this disease are warranted.

When determining the cause of poisoning by antidepressant drugs, the data of laboratory toxicological studies of biofluids for the presence of this group of drugs are of key importance. Aim. To develop the methods for determining the antidepressant drug trazodone in the blood and urine samples using high-performance liquid chromatography with a UV spectrophotometric detection, which is suitable for analytical diagnosis of the thymoleptics intoxications. Materials and methods. The model samples of human biofluids spiked with trazodone were studied. The antidepressant was isolated from the blood and urine by the liquid-liquid extraction with methylene chloride from the alkaline medium at pH 9. Concomitant endogenous impurities were removed by extraction with diethyl ether from the acidic medium at pH 1. In the study of the blood the erythrocyte mass was pre-precipitated with the help of 10 % of trichloroacetic acid solution. Chromatographic analysis was performed on a microcolumn chromatograph using a column with a reversed-phase of C18. Results. The absolute retention time of trazodone in extracts from the model samples of biofluids was 17.91±0.09 min. The quantitative content of trazodone was determined at 250 nm by the calibration dependence of the chromatographic peak area on the concentration (μg/ml) y=(1.74∙10-3±1∙10-5)x. Under the indicated extraction conditions, 35±4 % and 78±4 % of trazodone were isolated from the blood and urine, respectively. Conclusions. The methods of trazodone isolation from the biofliuds by liquid extraction followed by the determination of the drug by high performance liquid chromatography with a multiwave UV spectrophotometric detection have been developed. The methods are recommended for using in the practice of forensic and clinical toxicology.

Low arousal threshold plays a part in the pathogenesis of obstructive sleep apnea (OSA) and may be improved by sedatives. Sedative antidepressants are frequently prescribed for stroke patients due to their high prevalence of insomnia and depression. However, the effect of sedative antidepressants on the severity of OSA in stroke patients has not been studied well. In a double-blinded randomized crossover pilot study, 22 post-acute ischemic stroke patients (mean age, 61.7 ± 10.6 y) with OSA received 100 mg of trazodone or a placebo just before polysomnography, with approximately 1 week between measures. The study also measured baseline heart rate variability and 24-h ambulatory blood pressure. Administration of trazodone significantly increased the percentage time of slow-wave sleep (31.5 ± 13.2 vs. 18.4 ± 8.7%; P 50%; n = 7/22) had predominant OSA during rapid-eye-movement sleep and decreased sympathetic tone, as reflected in significantly lower mean blood pressure, diastolic blood pressure, and normalized low-frequency power. Obstructive sleep apnea with comorbid ischemic stroke may be a distinctive phenotype which responds quite well to trazodone, decreasing OSA severity without increasing nocturnal hypoxia. Clinicaltrials.gov: NCT04162743, 2019/11/10.

Trazodone (TRZ) is a commonly prescribed antidepressant with significant off-label use for insomnia. A recent drug screening revealed that TRZ interferes with sterol biosynthesis, causing elevated levels of sterol precursor 7-dehydrocholesterol (7-DHC). Recognizing the well-documented, disruptive effect of 7-DHC on brain development, we designed a study to analyze TRZ effects during pregnancy. Utilizing an in vivo model and human biomaterial, our studies were designed to also account for drug interactions with maternal or offspring Dhcr7 genotype. In a maternal exposure model, we found that TRZ treatment increased 7-DHC and decreased desmosterol levels in brain tissue in newborn pups. We also observed interactions between Dhcr7 mutations and maternal TRZ exposure, giving rise to the most elevated toxic oxysterols in brains of Dhcr7+/− pups with maternal TRZ exposure, independently of the maternal Dhcr7 genotype. Therefore, TRZ use during pregnancy might be a risk factor for in utero development of a neurodevelopmental disorder, especially when the unborn child is of DHCR7+/− genotype. The effects of TRZ on 7-DHC was corroborated in human serum samples. We analyzed sterols and TRZ levels in individuals with TRZ prescriptions and found that circulating TRZ levels correlated highly with 7-DHC. The abundance of off-label use and high prescription rates of TRZ might represent a risk for the development of DHCR7 heterozygous fetuses. Thus, TRZ use during pregnancy is potentially a serious public health concern.

Purpose: We examined whether patients are appropriately screened for previous prolonged erections or priapism and counseled about trazodone complications, specifically prolonged erections and priapism, prior to trazodone treatment. Materials and Methods: We identified patients under the age of 50 on trazodone as of February 27, 2019 at the VA New Jersey Health Care System. Patients were asked about information provided to them prior to medication initiation, occurrence of prolonged erections/priapism, and reporting rate of side effects. Results: Two hundred and twenty nine out of five hundred and twenty four male patients agreed to participate in the study. Forty three out of two hundred and twenty nine of patients were informed about the side effects of prolonged erections and 37/229 of patients were informed of risk of priapism prior to treatment. Only 17/229 of patients were asked if they had had any episodes of prolonged erection or priapism in the past. Eighteen patients developed prolonged erection while taking trazodone. Only 5/18 patients who had developed prolonged erections informed their physicians. Conclusions: Only a fraction of patients were properly screened for previous prolonged erections or priapism and properly informed about the side effects of trazodone. Urologist should better educate trazodone prescribers, such as family medicine and psychiatric colleagues, regarding the side effects of trazodone. It is imperative that prescribing physicians appropriately screen and educate patients prior to trazodone initiation and instruct patients to report any treatment side effects to avoid potential long-term adverse outcomes.

Objectives To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. Materials and methods 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. Results Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. Conclusion To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

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

Background and objectives Zolpidem, a nonbenzodiazepine hypnotic, and trazodone, a sedating antidepressant, are the most common medications used to treat insomnia in the United States. Both drugs have side effect profiles (e.g., drowsiness, dizziness, and cognitive and motor impairment) that can heighten the risk of falls and fractures. Despite widespread zolpidem and trazodone use, little is known about the comparative safety of these medications in patients receiving hemodialysis, a vulnerable population with an exceedingly high fracture rate. Design, setting, participants, & measurements Using data from the United States Renal Data System registry (2013–2016), we conducted a retrospective cohort study to investigate the association between the initiation of zolpidem versus trazodone therapy and the 30-day risk of hospitalized fall-related fractures among Medicare-enrolled patients receiving maintenance hemodialysis. We used an active comparator new-user design and estimated 30-day inverse probability of treatment-weighted hazard ratios and risk differences. We treated death as a competing event. Results A total of 31,055 patients were included: 18,941 zolpidem initiators (61%) and 12,114 trazodone initiators (39%). During the 30-day follow-up period, 101 fall-related fractures occurred. Zolpidem versus trazodone initiation was associated with a higher risk of hospitalized fall-related fracture (weighted hazard ratio, 1.71; 95% confidence interval, 1.11 to 2.63; weighted risk difference, 0.17%; 95% confidence interval, 0.07% to 0.29%). This association was more pronounced among individuals prescribed higher zolpidem doses (hazard ratio, 1.85; 95% confidence interval, 1.10 to 3.01; and risk difference, 0.20%; 95% confidence interval, 0.04% to 0.38% for higher-dose zolpidem versus trazodone; and hazard ratio, 1.60; 95% confidence interval, 1.01 to 2.55 and risk difference, 0.14%; 95% confidence interval, 0.03% to 0.27% for lower-dose zolpidem versus trazodone). Sensitivity analyses using longer follow-up durations yielded similar results. Conclusions Among individuals receiving maintenance hemodialysis, zolpidem initiators had a higher risk of hospitalized fall-related fracture compared with trazodone initiators. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_12_18_CJN10070620_final.mp3

Introduction: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics. Areas covered: This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I-IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.Expert opinion: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.

Given the strong bidirectional relationship between sleep disruption and psychiatric conditions, particularly between depression and insomnia, it is important to understand the beneficial and potentially harmful effects of antidepressants on sleep. Antidepressants remain commonly used off-label for the treatment of chronic insomnia. SSRI, SNRI, and TCA drugs reduce REM sleep and increase REM latency. TCA drugs can be sedating or stimulating. Low-dose doxepin improves sleep continuity and is FDA approved for the treatment of chronic insomnia. Trazodone, the most commonly used antidepressant, reduces the number of awakenings. Preclinical studies have shown potential antidepressant effects of orexin antagonists, which are used to treat insomnia. Data on the usage of most antidepressants for insomnia remain limited. Low-dose doxepin is the only FDA-approved antidepressant for insomnia. Orexin antagonists may represent a future approach for treatment of both depression and insomnia.

Purpose of review Insomnia and hypersomnia are conditions with multifactorial causes that can be difficult to treat. There have been recent developments and changes in the treatment of both conditions, including the addition of some agents that have a novel mechanism of action. This review summarizes recent changes and highlights pertinent updates. Recent findings Benzodiazepine receptor agonists received a warning in 2019 regarding the possibility of complex sleep behaviors, such as sleepwalking. Zolpidem has been marketed in new dosage forms that include sublingual tablets and oral spray formulations. Orexin receptor antagonists appear to be well tolerated with a good safety profile. Suvorexant received an approval for the treatment of patients with comorbid insomnia and dementia. Lemborexant was demonstrated to be effective for maintenance insomnia. Trazodone was shown to affect the oligomerization of tau proteins thus suggesting potential implications in attenuating dementia pathology. Pitolisant, a novel histamine-3 receptor antagonist/inverse agonist, gained approval for the treatment of excessive daytime sleepiness in adults with narcolepsy as well as obstructive sleep apnea. Solriamfetol, a new norepinephrine and dopamine reuptake inhibitor, was approved for hypersomnolence based on good efficacy, but with cardiovascular warnings. Summary Recent advancements in the treatment of insomnia includes agents with novel mechanisms, new indications, and new dosage forms. Risk of complex sleep behaviors, and possible next-day driving impairment, should be discussed for all agents used for insomnia, including orexin receptor antagonists. Novel agents also are available for hypersomnia and there are options beyond traditional stimulants that may have great utility.

Wasielewska Magdalena. Comparison of the mechanisms of action of antidepressants and their side effects. Journal of Education, Health and Sport. 2020;10(8):260‑267. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2020.10.08.030 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2020.10.08.030 https://zenodo.org/record/3992426 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2020; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 01.08.2020. Revised: 05.08.2020. Accepted: 20.08.2020. Comparison of the mechanisms of action of antidepressants and their side effects Magdalena Wasielewska Magdalena Wasielewska; ORCID: 0000-0001-8638-3732; E-mail: w.magdalena1@gazeta.pl Nicolaus Copernicus University in Toruń Collegium Medicum in Bydgoszcz, ul. Jagiellońska 13-15, 85-067 Bydgoszcz, Major Pharmacy Abstract Introduction: There are 4 groups of LPs divided according to the mechanism of action. They act on the brain by modulating monoaminergic systems, causing a series of side effects such as insomnia, sedation, anxiety, and a problem of a sexual nature. By appropriately selecting the drug and its dose, the negative effects of the therapy can be avoided. Aim : Comparison of the mode of action of a drug from a given group of antidepressants and description of its side effects. State of knowledge : An example from the first group of drugs with a receptor mechanism of action is trazodone - it acts on many receptors. The combined effect of the drug on all three receptors will significantly improve sleep in all its phases. It is as effective a drug as TLPD, and due to the lack of anticholinergic and cardiotoxic effects, it has a better tolerance and safety profile. It works quickly and improves sleep parameters, which is responsible for faster improvement of the patient's mental state. An example of a drug from the second group of drugs with a different mechanism of action is agomelatine. It is a synthetic analog of melatonin. The simultaneous agonist action on one receptors and antagonist action on the other causes a number of changes in the CNS, which are responsible for the antidepressant effect. The effects of the treatment can be seen after 2 weeks of use. The drug of the third group neurotransmitter reuptake inhibitors there is bupropion. It intensifies the dopaminergic transmission. It does not disturb the sexual sphere, but increases insomnia as a side effect. Summary : By selecting the appropriate LP and its dose, side effects can be avoided. Key words: depression; mental disorders; antidepressants; side effects

SATB2-associated syndrome is an autosomal dominant, multisystemic disorder with associated sleep and behavioral abnormalities. Evidence is limited on appropriate management strategies in this population. We describe the medical management of a four-year-old child with poor sleep and significant behavioral problems. After failing initial treatment with melatonin, we initiated treatment clonidine along with high doses of trazodone for sleep. Daytime treatment with quetiapine was added to successfully manage behavioral issues. We present the challenges associated with treatment strategies in children with this syndrome.

Background Priapism is an adverse drug reaction (ADR) associated with phosphodiesterase type 5 inhibitors (PDE5is) in the treatment of erectile dysfunction. Aim The purpose of this study was to identify the true data about PDE5i-associated priapism to properly counsel patients. Methods We queried the U.S. Food and Drug Administration (FDA) Adverse Reporting System Public Dashboard to identify cases of drug-induced priapism among medications commonly associated with priapism. Next, a systematic review and analysis of publications describing cases of drug-induced priapism were carried out. Outcomes The main outome of this study is incidence of PDE5i-induced priapism. Results We found 411 cases of drug-induced priapism secondary to Viagra, Cialis, or Levitra reported to the Food and Drug Administration since 1998. Compared with PDE5is, drug-induced priapism was 2.6 (n = 1,065) and 2.0 times (n = 817) more commonly reported for second-generation antipsychotics and the antidepressant/sleep aid trazodone, respectively. A total of 240 manuscripts describing cases of drug-induced priapism in patients with non-sickle cell disease were identified. PDE5i-induced priapism accounted for only 2.9% (n = 7) of drug-induced priapism cases. Second-generation antipsychotics (33.8%), a group of “other” medications (11.3%), and alpha-adrenergic antagonists (8.8%) accounted for the greatest percentage of published drug-induced priapism cases. Clinical Implications Extensive counseling about priapism as an ADR for PDE5i for the routine treatment of erectile dysfunction is likely unnecessary. Strengths & Limitations The study used national-level data to identify drug-induced priapism cases. Reported and published cases of drug-induced priapism may reflect more severe and atypical cases of this ADR, which may have underestimated our results. Conclusion PDE5i-induced priapism is a rare event. Drug-induced priapism should be attributed to a wider spectrum of medications that can cause this condition.

Erectile dysfunction is one of the most common side effects of methadone affecting more than half of methadone patient population. The problem is associated with prominent reduced quality of life. Erectile dysfunction may perpetuate greater problem if left untreated as patients may opt to use harmful self-treatment such as abusing methamphetamine. This illicit drug use to overcome the side-effects of methadone may lead to polysubstance use disorder that further compromise addiction therapy. To overcome this issue, both practitioners and patients play a major role in the management of erectile dysfunction. Patient awareness regarding erectile dysfunction and its impact as well as doctor’s active intervention to detect erectile dysfunction, are essential to improve the detection rate and management of erectile dysfunction. Frequent screening of erectile dysfunction and its risk factors will help with the identification of patients suffering from erectile dysfunction. Multiple treatments options such as bupropion, trazodone and many more are available to treat erectile dysfunction which will be further explored in this review.

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

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

The primary objective of this study was to investigate the association between antidepressants use and the risk of acute myocardial infarction (AMI). METHODS: We conducted a nested case–control study using a primary care database over the period 2002–2015. From a cohort of patients aged 40–99 years, we identified incident AMI cases and randomly selected 5 controls per case, matched to cases for exact age, sex and index date. Exposure to antidepressants were categorised as current, recent, past and nonusers. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were computed using conditional logistic regression to assess the association between the current use of different antidepressants subgroups and AMI as compared to nonuse. Dose and duration effects were explored. RESULTS: Totals of 24 155 incident AMI cases and 120 775 controls were included. The current use of antidepressants as a group was associated with a reduced risk (AOR = 0.86; 95% CI: 0.81–0.91), but mainly driven by selective serotonin reuptake inhibitors (AOR = 0.86; 95% CI:0.81–0.93). A reduced risk was also observed with trazodone (AOR = 0.76;95% CI: 0.64–0.91), and clomipramine (AOR = 0.62; 95% CI: 0.40–0.96), whereas no significant effect was observed with other antidepressants. A duration‐dependent effect was suggested for selective serotonin reuptake inhibitors, trazodone and clomipramine, while there was no clear dose‐dependency. CONCLUSION: This study suggests that current use of antidepressants interfering selectively with the reuptake of serotonin, and those antagonizing the 5‐HT(2A) receptor, are associated with a decrease in AMI risk and should be the antidepressants of choice in patients at cardiovascular risk.

Akathisia is one of the most prevalent and distressing adverse effects associated with antipsychotic drug treatment. Propranolol, a non-selective beta-adrenergic receptor antagonist, is currently considered a first-line treatment for antipsychotic-induced akathisia (AIA). Surprisingly, the evidence for its anti-akathisia effect is modest. Propranolol’s side effects (e.g. orthostatic hypotension, bradycardia), contraindications (e.g. asthma) and increased complexity in titration schedules limit its use in some patients. Anticholinergic agents and benzodiazepines merely provide symptomatic relief in patients with AIA. Effective and well-tolerated treatment remains a major unmet need in akathisia and warrants a search for new anti-akathisia agents. Accumulating evidence during the last two decades indicates that agents with marked postsynaptic serotonin 5-HT2a receptor antagonism (ritanserin, cyproheptadine, trazodone, mianserin, mirtazapine) may represent a new class of potential anti-akathisia remedies. Among these agents, low-dose mirtazapine (7.5 mg or 15 mg once daily) has demonstrated the most compelling evidence for therapeutic efficacy. In this narrative review we highlight the clinical significance of AIA, outline major approaches for its management and propose a practical algorithm for its treatment.

BACKGROUND: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose. METHODS: This was a prospective multicenter cohort study at >50 hospital sites across the U.S. using the ToxIC Registry between 2015–18. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease). RESULTS: From 25,303 patients screened, 6,473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron. CONCLUSIONS: This large U.S. cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.

Introduction Treatment of hypoactive sexual desire disorder (HSDD) remains unfulfilled. The only approved medication, flibanserin (FLI), is highly underused owing to concerns about central nervous system (CNS) depression and interactions. Trazodone (TRZ), which is not often used for sexual problems, has evidence suggesting efficacy but similar concerns. Aim To explore whether the pharmacologic similarities between TRZ and FLI could allow treatment of HSDD without CNS depression. Methods A literature search on TRZ was performed for clinical effects and to facilitate pharmacologic considerations relating to doses for HSDD and CNS depression. Main Outcome Measure The main measures were threshold doses for sedative-hypnotic effects, and calculated doses for occupy 20% of agonist receptors and 70% of antagonist receptors, considering 5HT1A, 5HT2A, 5HT2C, and α1 receptors for sexual benefits and 5HT2A, α1, and histamine type 1 receptors for CNS depression. Results 3.5–19.2-mg extended-release (XR) TRZ daily (bioequivalent to 1.2–6.4-mg immediate-release [IR] TRZ 3 times a day) is estimated to be the minimum effective dose for improving sexual desire and arousal; 75 mg (25-mg IR) appears to be the threshold dose for CNS depression. Conclusion Although tested only in much larger dose strengths, the optimal dose of XR TRZ for HSDD according to receptor and PK data appears to be about 4–20 mg. HSDD or arousal problems might be treated without over-sedation with XR 150-mg TRZ matrix tablets quartered to 37.5 mg daily or 50-mg IR TRZ tablets quartered to 12.5 mg given 2–3 times daily or as needed for arousal problems. Interindividual sensitivity might require varying the dose. Mechanistically rational adjuncts (eg, bupropion or dopaminergics) might augment response. Pyke RE. Trazodone in Sexual Medicine: Underused and Overdosed? Sex Med Rev 2020;8:206–216.

Companion dogs housed in animal shelters are subject to a great number of uncontrollable and unalterable stressors. To combat these stressors and the associated immunosuppression that can result in high rates of contagious disease in sheltered dogs, a large open admission municipal animal shelter in New York City introduced trazodone hydrochloride, a serotonin receptor antagonist and reuptake inhibitor, to help reduce their transitional stress. Dogs were given low doses of trazodone at intake (5 mg/kg), one to two doses within 48 hours of arrival. Prevalence of illness was calculated for two time periods at the Brooklyn and Manhattan Care Center locations (N = 1,766): November and December 2018, when trazodone was administered to the population, and a historical control in November and December 2017 and 2016, when no trazodone was administered. A statistically significant difference in the percentage of sick dogs was found when comparing the No Trazodone group (2016/2017) and Trazodone treatment group in 2018 (Chi2 [1, N = 1766] = 19.4, P

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

Acute compartment syndrome occurs most frequently in connection with injuries, terminal or chemical damage of tissues, ischemia,the activity of toxins or in patients with tissue ischemia or muscle necrosis. Clinical findings have found pronounced pain, followed by paresthesias, pallor, and paresis. Decreased pulsation of arteries has also been a frequent finding. In severe forms decompressive fasciotomy has been indicated within the first 12–24 hours after diagnosis. In the following paper, the authors present the case report of a 68-year woman who swallowed 1500 mg of trazodone as an attempt at suicide. After 12 hours her husband found her lying on the carpet with compression of the left arm under the trunk. The patient was treated conservatively and followed clinically,examined by ultrasonography, EMG and finally MRI. ‎Syndrom akutního kompartmentu se vyskytuje nejčastěji v souvislosti se zraněními, terminálním nebo chemickým poškozením tkání, ischemií, aktivitou toxinů nebo u pacientů s tkáňovou ischemií nebo svalovou nekrózou. Klinické nálezy zjistily výraznou bolest, následovanou parestézií, bledost a parézou. Častým nálezem byla také snížená pulzace tepn. V těžkých formách byla dekompresní fasciotomie indikována během prvních 12-24 hodin po diagnóze. V následujícím článku autoři prezentují případovou zprávu 68leté ženy, která spolkla 1500 mg trazodonu jako pokus o sebevraždu. Po 12 hodinách ji manžel našel ležet na koberci s kompresí levé paže pod kufrem. Pacient byl léčen konzervativně a klinicky sledován, vyšetřen ultrasonografií, EMG a nakonec MRI.‎

Background The objective of this study was to explore the underlying etiologies associated with the resolution and improvement of delirium in ill‐hospitalized cancer patients. Methods We conducted a secondary analysis of a multicenter, prospective, observational study to estimate the effectiveness of pharmacotherapy for delirium. Participants were cancer patients with delirium. We assessed the Delirium Rating Scale, Revised‐98 (DRS‐R98) severity scale score at baseline and three days after pharmacotherapy initiation. Delirium resolution was defined as a DRS‐R98 severity scale score ≤9, and improvement was defined as ≥50% reduction at Day 3. Results We enrolled 566 patients (491 patients had performance status of 3 or 4). The resolution and improvement rates in all patients were 22.6% and 19.3%, respectively. Univariate analysis determined that nonrespiratory infection (OR 2.18, 95% CI 1.38‐3.45) was significantly associated with greater resolution, while dehydration (0.40, 0.19‐0.87), organic damage to the central nervous system (CNS) (0.32, 0.43‐0.72), hypoxia (0.25, 0.12‐0.52), and hyponatremia (0.34, 0.12‐0.97) were significantly associated with no resolution. Potential causes associated with delirium improvement were nonrespiratory infection (1.93, 1.19‐3.13), organic damage to the CNS (0.40, 0.18‐1.90), and hypoxia (0.32, 0.16‐0.65). After multivariate analysis, dehydration (0.34, 0.15‐0.76), organic damage to the CNS (0.25, 0.10‐0.60), and hypoxia (0.29, 0.14‐0.61) were significantly associated with no resolution. Conclusions Delirium caused by nonrespiratory infection may be reversible, while delirium associated with dehydration, organic damage to the CNS, hypoxia, or hyponatremia seems to be irreversible in ill‐hospitalized cancer patients., We confirmed that delirium caused by nonrespiratory infection can be reversible, while delirium associated with dehydration, organic damage to the central nervous system, hypoxia, and hyponatremia is likely irreversible.

none 4 si Background: Benzodiazepines and other hypnotic alternatives are associated with increased risks of adverse events. Heightened awareness of risks may have changed prescribing habits over the years. However, these trends are not fully described, especially in vulnerable people such as multimorbid older adults. Objective: We aimed to describe the annual prevalence of benzodiazepine and other hypnotic use in relation to multimorbidity among older adults in the province of Quebec, Canada, from 2000 to 2016. Method: We conducted a population-based study using the Quebec Integrated Chronic Disease Surveillance System. We included all individuals aged ≥66 years covered by the public drug plan. For each year, we evaluated the sex- and age-standardized proportion of benzodiazepine and other hypnotic users, defined as individuals with at least one drug claim in the year. We stratified our results according to multimorbidity and used log-binomial regression to study trends. Results: The proportion of individuals using benzodiazepines decreased from 34.8% in 2000 to 24.8% in 2016 (p for trend

Patient: Female, 55-year-old Final Diagnosis: Trazodone overdose Symptoms: Altered mental status • seizure • shock • arrhythmia Medication: — Clinical Procedure: — Specialty: Toxicology Objective: Rare disease Background: Trazodone is widely used in the treatment of depression, anxiety, and insomnia. It is thought to have a safe cardiac profile due to the relative lack of anticholinergic effects. Publications about cardiac toxicities of trazodone are scant. Case Report: A 55-year-old woman presented with acute disorder of consciousness secondary to an intentional trazodone overdose. She was found to have seizure activity without cerebral edema. The initial electrocardiogram was unremarkable, with a normal QTc interval. She eventually developed QTc prolongation that evolved into ventricular tachycardia, and then into a transient right bundle-branch block, left anterior fascicular block, and variable degrees of atrioventricular nodal blocks at 12–24 h after ingestion. She then developed generalized tonic-clonic seizures, cardiogenic shock, and respiratory arrest. She was intubated and treated with antiepileptics, norepinephrine, and dopamine infusion. QTc interval prolongation gradually resolved and the various forms of heart block did not recur after at 24–36 h. She did not require transcutaneous pacing, and was successfully extubated with intact neurological function. Conclusions: Fatal arrhythmias can occur in trazodone overdose. Close monitoring and supportive care are crucial for patient survival.

Background: Melatonin has been associated with a wide variety of cellular, neuroendocrine, and neurophysiological processes. Clinical studies have reported the use of melatonin as an agent ...

An 18 year-old woman presented to an outside hospital with seizure activity after a massive ingestion of lamotrigine, bupropion, trazodone, buspirone, and possibly isoretinoin. Her initial vital signs were remarkable for tachycardia (120 bpm). She was intubated for airway protection. For treatment of status epilepticus, she received a total of 12 mg of IV lorazepam along with a lorazepam infusion titrated to 15 mg/hr, a propofol infusion of unknown dosing, and phenobarbital 650 mg. She was transferred to a receiving hospital. Her initial ECG at the receiving hospital showed a QRS of 117 ms which narrowed with 50 mEq of sodium bicarbonate after approximately 6 hours. She required norepinephrine intermittently for blood pressure support for approximately 2 days. The patient had no dysrhythmias. EEG showed no epileptiform activity from approximately 11 hours-32 hours post ingestion. At the receiving hospital, her serum lamotrigine concentration was 109 mcg/mL (reference 3.0-14.0 mcg/mL) 7 hours after ingestion. Her bupropion concentration was 92 ng/mL (reference 50-100 ng/mL). She was extubated on hospital day 5 and discharged to a psychiatric facility on hospital day 13.

BackgroundDuring the first wave of the coronavirus disease 2019 (COVID-19) pandemic, patients with confirmed cases in New York State accounted for roughly 25% of total US cases, with psychiatric hospital in-patients at particularly high risk for COVID-19 infection.AimsThe beneficial effects of mental health medications, such as selective serotonin reuptake inhibitors (SSRIs), on the severity of COVID-19 disease outcomes have been documented. Protective effects against infection have also been suggested for these medications. We therefore tested the hypothesis that medication use modifies the risk of COVID-19 infection in a long-stay, chronic in-patient psychiatry setting, where the potential for exposure was likely uniform across the facility, and where these medications were routinely prescribed.MethodThis was a retrospective cohort study of an adult psychiatric facility operated by the New York State Office of Mental Health. Current medication information and COVID-19 status was collected from electronic medical records for 165 people who were in-patients during the period January to July 2020, and logistic regression was employed to model the main effects of medication use on COVID-19 infection.ResultsA significant protective association was observed between antidepressant use and COVID-19 infection (odds ratio (OR) = 0.33, 95% CI 0.15–0.70, adjusted P < 0.05). Analysis of individual antidepressant classes showed that SSRI, serotonin-norepinephrine reuptake inhibitor and the serotonin-2 antagonist reuptake inhibitor classes of antidepressants, drove this protective effect. Exploratory analyses of individual antidepressants demonstrated an association between lower risk of infection and fluoxetine use (P = 0.023), as well as trazodone use (P = 0.001).ConclusionsThe novel finding of reduced COVID-19 infection risk for psychiatric in-patients taking antidepressants, suggests that antidepressants may be an important weapon in the continued fight against COVID-19 disease. This finding may become particularly salient for in-patient settings if vaccine-resistant strains of the virus appear.

Study Objectives It is common to provide insomnia patients a second treatment when the initial treatment fails, but little is known about optimal treatment sequences for different patient types. This study examined whether pre-treatment characteristics/traits predict optimal treatment sequences for insomnia patients. Methods A community sample of 211 adults (132 women; Mage = 45.6 ± 14.9 years) with insomnia were recruited. Patients were first treated with behavioral therapy (BT) or zolpidem (Zol). Non-remitting BT recipients were randomized to a second treatment with either Zol or cognitive therapy; non-remitting Zol recipients underwent BT or Trazodone as a second treatment. Remission rates were assessed at the end of the first and second 6-week treatments. We then compared the remission rates of dichotomous groups formed on the basis of gender, age, pretreatment scores on SF36 and Multidimensional Fatigue Scale, the presence/absence of psychiatric/medical comorbidities or pain disorders, and mean subjective sleep duration and efficiency within and across treatment sequences. Results Lower remission rates were noted for those: with a pain disorder, poor mental health perceptions, high MFI fatigue scores, and lower sleep times and efficiencies. Patients with a pain disorder responded best to the BT-to-Zol sequence, whereas patients with more mental impairment, severe fatigue, short sleep, and low sleep efficiency responded poorly to treatment starting with BT. Conclusions Pain, fatigue, poor mental health status, and subjective sleep duration and efficiency all affect response to different insomnia treatment sequences. Findings may guide clinicians in matching insomnia treatments to their patients. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT01651442, Protocol version 4, April 20, 2011, registered June 26, 2012, https://clinicaltrials.gov/ct2/show/NCT01651442?rslt=With&type=Intr&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&age=12&draw=2&rank=1.

Background Restless Legs Syndrome (RLS) is an annoying problem, has a noticeable impact on all perspective of the life. RLS attract spots to its discussion as it became a challenge in all societies. Also, antipsychotic (AP) and antidepressant drugs (AD) is well known as a cause of RLS, But RLS occurrence and its prevalence among psychiatric patients who receive the antipsychotic and antidepressant drugs is un known in Egypt. Aim of the Study To estimate rate of Restless legs Syndrome among psychiatric patients who receive Antidepressant & Antipsychotic drugs. And to assess severity of RLS if detected in those patients Subjects and Methods A descriptive cross-sectional, case control comparative observational study, included two hundred Patients who received AP and AD for more than one month and one hundreds of volunteers as a control group from Psychiatry department, Ain Shams University Hospitals and Al- Abbassyia Mental Hospital in Cairo, Egypt, in the period between October 2018 and April 2019, Using validated Arabic version of Structured Clinical Interview for DSM-IV (SCID-I), four items questionnaire that was recommended by International Restless Legs Syndrome Study Group (IRLSSG) Arabic version for RLS diagnosis and validated Arabic version of Restless Legs Syndrome Rating Scale (IRLS). Results Eighty-three (41.5%) of patient group who received AP & AD and fifteen (15%) individual of control group met the diagnostic criteria of RLS. There was high statistically significance between the two groups regarding RLS occurrence (P = 0.000). Severity fluctuated in patients’ group between moderate and sever (69.9 % & 30.1%) respectively, while in control group it fluctuated between mild and moderate (40 % & 60%) respectively with high statistically significance between the two groups regarding RLS severity (P = 0.000). Family history and smoking are a risk factors for developing RLS as (OR = 2.705) & (OR = 6.390) respectively. While Trazadone and Haloperidol had a protective role against RLS (OR = 0.393 & 0.415) respectively. Conclusion RLS occurrence was higher in patients who received AP and AD drugs and its severity was more fluctuant among those patients, antipsychotic and antidepressant can induce RLS or worse it in patients who had past history of RLS before receiving the medications. Smoking and family history were risk factors for developing or worsening of RLS in our study. Both Haloperidol and Trazadone drugs in our study had protective role against RLS.

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

What is known and objective Drug-induced long QT syndrome (diLQTS) is a rare but serious adverse drug reaction. Drug-drug interaction (DDI) is one of the risk factors for the development of diLQTS. However, the combinations of drugs that increase the risk of diLQTS have not been extensively investigated. This study was performed to analyse the potential DDIs that elevate the incidence of diLQTS using a spontaneous reporting system. Methods The Japanese Adverse Drug Event Report database from April 2004 to January 2020 was used to assess adverse event reports. We calculated the reporting odds ratio and 95% confidence interval for signal detection. Results and discussion Signals for concomitant use risk were detected in 31 drug combinations. Combinations of antipsychotics and antidepressants were the most common (olanzapine & fluvoxamine, olanzapine & trazodone, quetiapine & paroxetine, sulpiride & fluvoxamine, sulpiride & trazodone). Sixteen, 17 and 21 combinations were designated as requiring precaution for concomitant use in at least one of the package inserts in Japan, the United States and the United Kingdom, respectively, although no such precautions were described for the remaining combinations. On the contrary, a combination of bepridil & clarithromycin was categorized as "X (avoid combination)" and two combinations (chlorpromazine & haloperidol, amiodarone & metildigoxin) were classified as "D (modify regimen)" in the Lexicomp® risk rating. What is new and conclusion This study identified 31 combinations of drugs that may elevate the risk of diLQTS. The use of these drug combinations should be monitored more carefully in future.

Study Objectives It is known that antidepressant drugs can induce sleep disorders in patients, but little data exist about high or low-risk molecules. The aim was to study the frequency of antidepressant drug-induced sleep disorders (DISD) by molecule. Methods 77,391 patient comments for 32 antidepressant drugs were collected from drug review websites and screened for DISD. Association between drugs and nightmare disorder, restless legs syndrome, sleep paralysis, sleep terrors, sleep-related hallucinations, or sleep walking was expressed as relative proportion [proportional reporting ratio (PRR)]. A detailed analysis of the content of the dreams was also carried out. Results Amitriptyline, doxepin, fluvoxamine, mirtazapine, nortriptyline, trazodone, venlafaxine, and vilazodone were associated with a greater frequency of DISD compared to other antidepressants. Vilazodone heavily increased the probability of developing 5 of the 6 studied DISD (PRR 3.3 to 19.3) and mirtazapine increased the probability of developing 4 DISD (PRR 2.4 to 6.4). Bupropion and citalopram were associated with lower probabilities for 5 DISD (PRR 0.2 to 0.7). Sentiment analysis showed that patients described disturbing dreams for vilazodone or mirtazapine and strange but less negative dreams for bupropion, citalopram, or duloxetine. Conclusions Relative frequencies of sleep disorders were obtained for a vast panel of antidepressant drugs through an original analysis of user’s drug reviews on drug rating websites. Our results could guide clinicians in the appropriate choice of antidepressant drugs for high DISD-risk patients in need of such treatment. These results may however be cautiously taken, considering the uncertain reliability and generalizability of web-based data.

Pica in Alzheimer's disease (AD) makes it difficult for caregivers to provide care. However, few effective medications have been reported for pica in AD. We report a case of AD with pica that was successfully improved by trazodone and fluvoxamine. An 80-year-old woman with AD was admitted to our hospital due to aggravated pica, including eating weeds in the facility's garden and eating a dishwashing sponge. Her pica was accompanied by oral tendency, prosopagnosia, and placidity. She took rivastigmine and memantine, but these were ineffective for her pica. She was given olanzapine and perospirone, but both were discontinued due to over-sedation and severe extrapyramidal symptoms, respectively. We then administered trazodone and fluvoxamine, both of which have demonstrated effectiveness for pica in frontotemporal dementia (FTD). Her pica behaviors then disappeared without daytime sleepiness. In this case, pica with oral tendency, which was accompanied by prosopagnosia and placidity, may be interpreted as a partial symptom of Klüver–Bucy syndrome (KBS). KBS is often seen in FTD, but also occurs in late-stage AD. Our case together with previous reports showing that trazodone and fluvoxamine were effective for pica in FTD suggest that the same common drug therapy may be successful in pica with oral tendency, regardless of the subtype of dementia.

Background Benzodiazepine hypnotics and the related nonbenzodiazepine hypnotics (z-drugs) are among the most frequently prescribed medications for older adults. Both can depress respiration, which could have fatal cardiorespiratory effects, particularly among patients with concurrent opioid use. Trazodone, frequently prescribed in low doses for insomnia, has minimal respiratory effects, and, consequently, may be a safer hypnotic for older patients. Thus, for patients beginning treatment with benzodiazepine hypnotics or z-drugs, we compared deaths during periods of current hypnotic use, without or with concurrent opioids, to those for comparable patients receiving trazodone in doses up to 100 mg. Methods and findings The retrospective cohort study in the United States included 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015. Study endpoints were out-of-hospital (primary) and total mortality. Hazard ratios (HRs) were adjusted for demographic characteristics, psychiatric and neurologic disorders, cardiovascular and renal conditions, respiratory diseases, pain-related diagnoses and medications, measures of frailty, and medical care utilization in a time-dependent propensity score–stratified analysis. Patients without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone. Patients with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly increased relative to trazodone; findings were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes. Limitations included composition of the study cohort and potential confounding by unmeasured variables. Conclusions In US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone, study hypnotics were not associated with mortality. With concurrent opioids, benzodiazepines and z-drugs were associated with increased out-of-hospital and total mortality. These findings indicate that the dangers of benzodiazepine–opioid coadministration go beyond the documented association with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought., In a retrospective cohort study, Dr. Wayne Ray and colleagues investigate concurrent opioid and hypnotic use and mortality in older adults in US., Author summary Why was this study done? Benzodiazepines and the related z-drugs are sleep medications commonly prescribed for persons 65 years of age or older. Both can interfere with breathing, which, in turn, may cause irregular heartbeat and deaths. Opioid painkillers, often used with sleep medications, also interfere with breathing and thus could increase the likelihood of deaths with benzodiazepines or z-drugs. Trazodone, an antidepressant that in low doses often is prescribed for insomnia, has not been found to affect breathing and thus may be safer for older patients, particularly for those also taking opioids. What did the researchers do and find? We identified 400,924 persons in the US Medicare program 65 or older who began treatment with benzodiazepine, z-drug, or trazodone sleep medications. For patients without and with opioid use, we compared the rate of out-of-hospital deaths—often related to heart problems—and total mortality during treatment with benzodiazepines and z-drugs to that for trazodone. For patients with opioid exposure, benzodiazepines were associated with respective 302% and 221% increases in out-of-hospital and total mortality, and z-drugs were associated with respective 98% and 65% increases in out-of-hospital and total mortality. What do these findings mean? In older populations, the risks of concurrent benzodiazepine–opioid exposure go beyond the known increased likelihood of overdose, suggesting that greater efforts are needed to prevent use of this medication combination. Patients and clinicians should be aware that in combination with opioids, the z-drugs, thought to be relatively safe, may increase the risk of death.