Administration Of Trazodone Research Articles

Evaluation of the sedative properties of oral trazodone, gabapentin or their combination in healthy cats.

Sedation before veterinary visits is advocated to help reduce fear and anxiety in cats and facilitate safe handling. The aim of this study was to evaluate the effectiveness of trazodone, gabapentin and a trazodone/gabapentin combination for oral sedation in healthy feline patients before blood donation. A total of 21 cats were included in the study. Baseline sedation scores were obtained, and cats were randomly assigned to receive oral trazodone at 5 mg/kg (T), oral gabapentin at 10 mg/kg (G), their combination (TG) or placebo (control group). A sedation score was obtained 1 h after drug administration. A blood sample was obtained at the time of blood collection for quantification of drug plasma concentrations. Agreement between observers was tested with a Cohen's Kappa test. Sign tests to compare change within treatment and a Skilling-Mack rank ANOVA to test for differences between groups were performed to compare pre- and post-sedation scores as well as a magnitude of differences over time between the groups. A Spearman's rank correlation coefficient test was used to correlate sedation scores with drug plasma concentrations. Post-sedation final scores were significantly higher only in the T (P = 0.022) and TG groups (P <0.001). The magnitude of change between pre- and post-sedation scores was larger in the TG (P <0.0032) and T groups (P <0.038) compared with the control group. There were no other significant differences between the groups. There was no correlation between drug plasma concentrations and sedation scores in any of the groups. Administration of oral trazodone alone at 5 mg/kg or in combination with gabapentin at 10 mg/kg resulted in significant sedation in healthy cats with no evident side effects. The degree of sedation was more profound when both drugs were combined, but a gabapentin dose of 10 mg/kg alone failed to provide significant sedation in this population.

Effect of antidepressants on ejaculation dysfunction in patients with depression and anxiety: A systematic review and network meta-analysis.

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

Adverse effects of trazodone in dogs on primary hemostasis and electrocardiogram: A single-blinded placebo-controlled crossover study.

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

The efficacy of trazodone in reducing stress related behaviours in hospitalised dogs or dogs confined postsurgery

Clinical bottom line Category of research Treatment. Number and type of study designs reviewed Three papers were critically reviewed. One was a prospective, randomised, blinded observational study, another was a randomised, placebo-controlled clinical trial, and the last was a non-randomised prospective, open-label clinical trial. Strength of evidence Weak. Outcomes reported The administration of trazodone to hospitalised dogs reduced several observed stress related behaviours compared to a control group that was environmentally matched to the treatment group (Gilbert-Gregory et al., 2016). In dogs subjected to postsurgical confinement at home, trazodone administration was not more effective at reducing stress related behaviours compared with a placebo in one study (Gruen et al., 2017); however, it was effective when observed in a non-placebo controlled clinical trial (Gruen et al., 2014). Further investigation with a larger sample size would assist in strengthening the evidence of an association between trazodone administration and a reduction in the behavioural signs of stress in dogs. Conclusion The available evidence weakly supports the hypothesis that administration of trazodone is an effective treatment in reducing stress related behaviours in hospitalised dogs and dogs confined post-surgery, and further studies are required to confirm its efficacy. The quality of the evidence when hospitalised dogs was studied was moderate (Gilbert-Gregory et al., 2016), however in dogs studied that were confined postsurgery, the evidence is weaker (Gruen et al., 2014; Gruen et al., 2017). Different trazodone doses were evaluated in the studies and so further studies focusing on dose effects are required to determine appropriate dose rates. Further studies also need to be conducted to evaluate the appropriate length of time that trazodone should be given prior to a stressful event, as well as whether trazodone needs to be used in conjunction with other anxiolytic drugs to optimise efficacy. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Neuroprotective Effects of Selegiline Agent Methamphetamine-Prompted Mood-Related Behavior Disorder Mediated Via 5-HT2 and D2 Receptors.

Many previous studies demonstrated that methamphetamine (METH) abuses can cause mood-related behavioral changes. Previous studies indicated neuroprotective effects of Selegiline. Seventy male Wistar rats were randomly divided into eight groups (10 rats in each group). Group 1 and Group 2 received normal saline and methamphetamine (10 mg/kg) for 21 days, respectively. Groups 3, 4, and 5 were treated simultaneously with methamphetamine and Selegiline with doses of 10, 15, and 20 mg/kg for 21 days. Groups 6 and 7 are methamphetamine-dependent groups which received 15 mg/kg of Selegiline with haloperidol (as D2 receptor antagonist) and trazodone (as 5-HT2 receptor antagonist) for 21 days, respectively. In days 23 and 24, elevated plus maze (EPM) and open-field test (OFT) were conducted to assess motor activity and mood (anxiety and depression) levels. METH as 10 mg/kg causes reduction of rearing number, ambulation distances, time spent in central square and also number of central square entries in OFT. Also METH administration causes decreases of time spent in open arm and number of open arm entries and increases of time spent in closed arm and number of closed arm entries in EPM. In contrast, Selegiline (of 10, 15, and 20 mg/kg) inhibited behavioral effects of methamphetamine in both OFT and EPM. Also administration of haloperidol and trazodone inhibited these behavioral protective effects of Selegiline and caused decrease of OFT behaviors (rearing number, ambulation distances, time spent in central square, and also number of central square entries) and also caused decreases of spend times in open arm, number of open arm entries, and also increased closed arm time spending and number of entries in closed arm in EPM. Current research showed that Selegiline via mediation of D2 and 5-HT2 receptors inhibits METH-induced neurobehavioral changes, mood-related behavior, and motor activity disturbances.

The effect of preanaesthetic oral trazodone hydrochloride on the induction dose of propofol: a preliminary retrospective study

ObjectiveTo determine whether the administration of trazodone to dogs 2 hours prior to radiotherapy treatment reduced the dose of propofol required to induce anaesthesia. Study designRetrospective, crossover, case-matched study. AnimalsRecords of 30 client-owned dogs. MethodsAnaesthetic records from all dogs undergoing weekly radiotherapy treatment between January 2020 and December 2020 were retrospectively assessed. All dogs were premedicated with 10 μg kg–1 alfentanil and 12 μg kg–1 atropine intravenously (IV) and anaesthesia was induced with IV propofol. In part 1, the propofol induction dose was compared between anaesthetics when trazodone was administered prior to the anaesthetic (T) versus not (NT). For part 2, control dogs not administered trazodone during the treatment course were case-matched based on bodyweight and tumour location and type. The propofol induction dose was compared between the first (C1) and last (C2) anaesthetic to identify the effects of confounding factors. A Wilcoxon signed-rank test for repeated measurements was performed to identify any significant differences in the propofol induction dose between NT and T in the study dogs and between C1 and C2 in the control dogs. ResultsIn part 1, 15 study dogs that were administered trazodone prior to at least one anaesthetic were identified. A significant difference in propofol induction dose between groups NT and T was identified [3.3 (2.1–7.4) and 2.0 (1.5–5.0) mg kg–1, respectively; p = 0.003]. In part 2, 15 dogs were case-matched to the study cohort. The dose of propofol administered did not differ between the first and last anaesthetic [2.5 (1.6–6.4) and 2.6 (1.9–8.9) mg kg–1, respectively; p = 0.638]. Conclusions and clinical relevancePreanaesthetic trazodone administration reduced the induction dose of propofol compared to when it was not administered to dogs following premedication with IV atropine and alfentanil.

Improved Sleep, Memory, and Cellular Pathological Features of Tauopathy, Including the NLRP3 Inflammasome, after Chronic Administration of Trazodone in rTg4510 Mice.

Several cellular pathways contribute to neurodegenerative tauopathy-related disorders. Microglial activation, a major component of neuroinflammation, is an early pathologic hallmark that correlates with cognitive decline, while the unfolded protein response (UPR) contributes to synaptic pathology. Sleep disturbances are prevalent in tauopathies and may also contribute to disease progression. Few studies have investigated whether manipulations of sleep influence cellular pathologic and behavioral features of tauopathy. We investigated whether trazodone, a licensed antidepressant with hypnotic efficacy in dementia, can reduce disease-related cellular pathways and improve memory and sleep in male rTg4510 mice with a tauopathy-like phenotype. In a 9 week dosing regimen, trazodone decreased microglial NLRP3 inflammasome expression and phosphorylated p38 mitogen-activated protein kinase levels, which correlated with the NLRP3 inflammasome, the UPR effector ATF4, and total tau levels. Trazodone reduced theta oscillations during rapid eye movement (REM) sleep and enhanced REM sleep duration. Olfactory memory transiently improved, and memory performance correlated with REM sleep duration and theta oscillations. These findings on the effects of trazodone on the NLRP3 inflammasome, the unfolded protein response and behavioral hallmarks of dementia warrant further studies on the therapeutic value of sleep-modulating compounds for tauopathies.SIGNIFICANCE STATEMENT Dementia and associated behavioral symptoms such as memory loss and sleep disturbance are debilitating. Identifying treatments that alleviate symptoms and concurrently target cellular pathways contributing to disease progression is paramount for the patients and their caregivers. Here we show that a chronic treatment with trazodone, an antidepressant with positive effects on sleep, has beneficial effects on several cellular pathways contributing to neuroinflammation and tau pathology, in tauopathy-like rTg4510 mice. Trazodone also improved rapid eye movement (REM) sleep, the slowing of brain oscillations, and olfactory memory disturbances, which are all early symptoms observed in Alzheimer's disease. Thus, trazodone and compounds with REM sleep-promoting properties may represent a promising treatment approach to reduce the early symptoms of tauopathy and slow down disease progression.

Ефективність тразодону (Триттіко) у лікуванні пацієнтів з депресивними розладами та когнітивними порушеннями на фоні дисциркуляторної енцефалопатії

Статтю присвячено проблемі корекції депресивних розладів і легких когнітивних порушень у пацієнтів з хронічними порушеннями мозкового кровообігу. Наведено результати дослідження ефективності використання тразодону (препарат Триттіко) у даної категорії пацієнтів. Всі учасники дослідження (27 пацієнтів, середній вік 59,6 ± 7,3 року) отримували тразодон (Триттіко) в дозі 150 мг на ніч протягом 2 місяців, при цьому терапію хворі розпочинали з прийому 50 мг тразодону зі збільшенням дози протягом 7 днів до досягнення 150 мг на добу. Було встановлено, що на фоні тривалого (2 місяці) прийому тразодону (Триттіко) мало місце покращення когнітивного функціонування за даними MMSE в загальній групі та вірогідне зростання показників оперативної семантичної пам’яті, негайної і відстроченної асоціативної пам’яті та покращення ефективності процесів обробки інформації у хворих з легкими когнітивними порушеннями. Це дає підставу рекомендувати тразодон (Триттіко) для широкого використання в клінічній практиці з метою корекції депресивних розладів і легких когнітивних порушень у пацієнтів з хронічними порушеннями мозкового кровообігу.

Investigation of the effect of trazodone on spontaneous and acetylcholine-induced bladder detrusor smooth muscle contractions

Objective: The management of psychiatric patients is often complicated by medical comorbidities, complex pharmacological regimens, and side effects secondary to these regimens. In the current study, it was aimed to investigate the effects and mechanism of action of trazodone on rat bladder smooth muscle contractility in vitro. Method: Sixteen adult male Wistar albino rats were euthanized by the cervical dislocation method following ether anesthesia. Two muscle strips of 2 × 10 mm in size were prepared vertically from the bladder by opening a longitudinal incision from the neck of the bladder in the direction of the apex. The strips were tied properly and hung in the organ bath. All contraction amplitudes and frequencies were recorded. After a 45-min adaptation period, contractions were induced by applying 105 M acetylcholine (ACh) to all spontaneously contracting bladder strips. After 20 min, doses of trazodone (109 M vs 103 M) were given cumulatively. The resulting effects were recorded. Results: The groups were compared within themselves: a significant difference was found between the initial tensions in the group with ACh-induced contractions and the tensions after the administration of trazodone at 109, 108, 107, 106, 105, 104, and 103 M doses (p < 0.0001). In the group with spontaneous contractions, a significant difference was found between the initial tensions and the tensions after the administration of trazodone at 109, 108, 105, and 104 M doses (p < 0.0001). Conclusion: Results showed that trazodone had a significant inhibitory effect on bladder smooth muscle contractions in vitro, especially at concentrations of 104 and 103 M.

Trazodone improves obstructive sleep apnea after ischemic stroke: a randomized, double-blind, placebo-controlled, crossover pilot study.

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 100mg of trazodone or a placebo just before polysomnography, with approximately 1week 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 < 0.001) and improved almost all the parameters of OSA severity, including the apnea-hypopnea index (AHI, 25.4 ± 15.4 vs. 39.1 ± 18.4 events/h; P < 0.001), the respiratory arousal index (9.8 (5.8-11.95) vs. 14.1 (11.3-18.7) events/h; P < 0.001), and the minimum oxygen saturation (80.2 ± 9.1 vs. 77.1 ± 9.6%; P = 0.016). Responders to therapy (AHI reduced by > 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.

Pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs.

To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs. 6 healthy adult dogs. Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis. Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed. Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

Efficacy of oral trazodone slow release following intravenous administration in depressed patients: a naturalistic study.

Up to date, no studies in literature assessed the efficacy of a treatment schedule including i.v. trazodone followed by its oral administration. In light of this lack of evidence, the aim of the present study was to evaluate the efficacy and tolerability of trazodone, administered first i.v. and then orally in a sample of Major Depressive Disorder (MDD) patients. Thirty four patients underwent i.v. administration of trazodone (75-100 mg in 250 mL of saline) for 1 week. During the second week, oral extended-release formulation (150-300 mg per day) was added to the i.v. administration. Finally, extended-release trazodone was orally administration at doses of 150-300 mg per day. Psychometric scales were performed at baseline (T0), after 2 weeks (T1), 6 weeks (T2), after 3 months (T3), and 6 months (T4). The total sample included 34 subjects (14 males and 20 females). There was a statistically significant decrease in Hamilton Depression Rating Scale total scores from T0 to T1 (t=9.06; df=33), from T1 to T2 (t=4.96; df=29), from T2 to T3 (t=4.08; df=19), and from T3 to T4 (t=2.25; df=19); in Hamilton Anxiety Rating Scale total scores from T0 to T1 (t=8.79; df=33) and from T1 to T2 (t=5.61; df=29); in Montgomery-Asberg Depression Rating Scale total scores from T0 to T1 (t=9.30; df=33), from T1 to T2 (t=5.69; df=29), and from T2 to T3 (t=3.16; df=19). This finding confirms previous results on depression with concomitant anxiety symptoms: focusing on trazodone prolonged-release formulation, available data documented its efficacy in MDD.

Pharmacokinetics and selected pharmacodynamics of trazodone following intravenous and oral administration to horses undergoing fitness training

OBJECTIVE To measure concentrations of trazodone and its major metabolite in plasma and urine after administration to healthy horses and concurrently assess selected physiologic and behavioral effects of the drug. ANIMALS 11 Thoroughbred horses enrolled in a fitness training program. PROCEDURES In a pilot investigation, 4 horses received trazodone IV (n = 2) or orally (2) to select a dose for the full study; 1 horse received a vehicle control treatment IV. For the full study, trazodone was initially administered IV (1.5 mg/kg) to 6 horses and subsequently given orally (4 mg/kg), with a 5-week washout period between treatments. Blood and urine samples were collected prior to drug administration and at multiple time points up to 48 hours afterward. Samples were analyzed for trazodone and metabolite concentrations, and pharmacokinetic parameters were determined; plasma drug concentrations following IV administration best fit a 3-compartment model. Behavioral and physiologic effects were assessed. RESULTS After IV administration, total clearance of trazodone was 6.85 ± 2.80 mL/min/kg, volume of distribution at steady state was 1.06 ± 0.07 L/kg, and elimination half-life was 8.58 ± 1.88 hours. Terminal phase half-life was 7.11 ± 1.70 hours after oral administration. Horses had signs of aggression and excitation, tremors, and ataxia at the highest IV dose (2 mg/kg) in the pilot investigation. After IV drug administration in the full study (1.5 mg/kg), horses were ataxic and had tremors; sedation was evident after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of trazodone to horses elicited a wide range of effects. Additional study is warranted before clinical use of trazodone in horses can be recommended.

Trazodone in treatment of interferon-induced anxiety in persons with viral hepatitis C

IntroductionThe interferon therapy is associated with numerous adverse psychiatric effects, such as tension, irritability, insomnia, etc.GoalThe goal of this study was to examine the severity and the frequency of anxiety in persons with chronic hepatitis C receiving pegylated interferon alpha combined with ribavirin. We have also tried to assess the efficiency of trazodone in treatment of symptoms of anxiety in patients receiving pegylated interferon.MethodThe total of 36 patients whose diagnosis of chronic hepatitis C has been confirmed both serologically and patohistologically, receiving interferon therapy, ages 22 to 60, participated in this study. The control group consisted of 32 patients, all with same diagnosis, corresponding with those in the study group in terms of gender, age duration of the illness and the level of education. All patients received pegylated interferon alpha 2a, administered subcutaneously once per week, along with oral ribavirin. The research used the following instruments of clinical assessment: structural clinical interview–SCID, ICD–10; Hamilton anxiety rating scale–HAM-A, and the self-report scale for assessment of anxiety–state-trait anxiety inventory–STAI-Form Y. The testing using these instruments was conducted four weeks after the start of the treatment, then after eight weeks, after 12, 24 and 48 weeks, i.e. at the end of the treatment. The patients in the study group received 150–300 mg of trazodone per day, starting at the week 6 of interferon treatment.ResultsThe research showed that in the beginning of the interferon treatment approximately one quarter of the patients exhibited symptoms of anxiety in both groups. The administration of trazodone showed beneficial effects in reduction of anxiety induced by the treatment with pegylated interferon.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs

To determine the pharmacokinetics and hemodynamic effects of trazodone after IV and oral administration in dogs and bioavailability after oral administration. 6 adult Beagles. Dogs received trazodone HCl (8 mg/kg) orally and IV in a randomized controlled crossover design. Blood samples were collected at various times after administration. Heart rates and indirectly measured blood pressures of dogs and plasma concentrations and pharmacokinetics of trazodone were determined. Following IV administration, the mean ± SD elimination half-life, apparent volume of distribution, and plasma total body clearance were 169 ± 53 minutes, 2.53 ± 0.47 L/kg, and 11.15 ± 3.56 mL/min/kg, respectively. Following oral administration, the mean ± SD elimination half-life and absolute bioavailability were 166 ± 47 minutes and 84.6 ± 13.2%, respectively. Maximum plasma concentration following oral administration was 1.3 ± 0.5 μ/mL, and time to maximum plasma concentration was 445 ± 271 minutes. After IV administration, all dogs immediately developed transient tachycardia (184.3 ± 8.0 beats/min), and 3 of 6 dogs developed aggression. Increase in heart rate was significantly associated with increase in plasma drug concentration following IV administration. Results of this study indicated oral administration of trazodone resulted in acceptable absolute bioavailability, with substantial variability in time to maximum plasma concentration. Individualized approaches in dosing intervals may be necessary for dogs receiving oral trazodone. An orally administered dose of 8 mg/kg was well tolerated in dogs; IV administration of a dose of 8 mg/kg caused substantial adverse effects, including tachycardia and behavior disinhibition.

The Effect of Trazodone on Standardized Field Sobriety Tests

To evaluate the effects of a single dose of trazodone on the standardized field sobriety test (SFST). A randomized, double-blinded, repeated-measures study. Forty-five healthy adult subjects. University campus. The SFST consists of the horizontal gaze nystagmus, walk-and-turn, and one-leg stand tests. Subjects were administered a baseline SFST and at 2 hours after the administration of either trazodone 100mg (30 subjects) or acetaminophen 650mg (15 subjects). At 2 hours post drug administration, there were no statistical differences in failure rates between the trazodone and acetaminophen groups (53.3% vs 20.0%, p=0.054). However, the trazodone group exhibited more impairment clues within the individual tests of the SFST than the acetaminophen group. A one-time dose of trazodone 100mg does not result in an increased SFST failure rate at 2 hours postdosing compared to acetaminophen 650mg. However, the number of individual impairment clues detected is increased with trazodone. Trazodone 100mg may cause cognitive driving impairment.

Trazodone reduces the anticonvulsant action of certain classical antiepileptics in the mouse maximal electroshock model

BackgroundThe aim of the study was to examine effects of an acute and chronic treatment with trazodone, a serotonin antagonist and reuptake inhibitor (SARI), on the protective activity of four classical antiepileptic drugs provided in the maximal electroshock test in mice. MethodsElectroconvulsions were produced in mice by means of an alternating current (50Hz, 25mA, 0.2s) and delivered via earclip electrodes. Motor impairment in animals were assessed in the chimney test, and long-term memory deficits were quantified in the passive-avoidance task. Brain concentrations of antiepileptic drugs were analyzed by fluorescence polarization immunoassay. ResultsThe obtained results showed that a single administration of trazodone (up to 40mg/kg) did not influence the electroconvulsive threshold. In contrast, chronic treatment with the antidepressant (40mg/kg) significantly increased this parameter. Furthermore, both single and chronic administration of trazodone reduced the anticonvulsant effect of phenytoin and carbamazepine against the maximal electroshock. However, the antidepressant remained without effect on the anticonvulsant action of valproate and phenobarbital. Some interactions between trazodone and antiepileptic drugs may have a pharmacodynamic background. Both, acute and chronic treatment with the antidepressant diminished the brain concentration of phenytoin. Chronic trazodone lowered the brain levels of carbamazepine and phenobarbital. Moreover, acute and chronic trazodone increased the valproate concentration in the brain. As regards undesired effects, acute and chronic trazodone (40mg/kg), alone and in combination with phenytoin, significantly impaired long-term memory in tested animals, evaluated in the passive avoidance task. Acute trazodone (40mg/kg) alone and combined with phenytoin produced also significant motor deficits in mice, as measured in the chimney test. ConclusionThe obtained results allow to conclude that trazodone is not a good candidate for an antidepressant drug in epileptic patients.

Sentra PM (a Medical Food) and Trazodone in the Management of Sleep Disorders

Sleep disorders are a common and poorly treated disease state. This double blind, four arm placebo-controlled, randomized trial compared (1) low dose trazodone, (2) Sentra PM, a neurotransmitter based medical food, (3) the joint administration of trazodone and the medical food Sentra PM and (4) placebo. There were 111 subjects studied in 12 independent sites. Subjects underwent baseline screening, informed consent and an initial sleep questionnaire. After 14 days subjects underwent a second evaluation by questionnaire. At baseline and Day 14 the subjects underwent 24 hour ECG recordings that were analyzed in the frequency domain of heart rate variability. The specific high frequency parasympathetic autonomic nervous system activity was analyzed. The primary endpoints were sleep latency and parasympathetic autonomic nervous system improvement in sleeping hours. The results showed improvement in sleep latency for the Sentra PM and combination of Sentra PM and trazodone (−41 and −56 minutes P < 0.001). There was an improvement in quality of sleep for the amino acid formulation Sentra PM and the combination (3.86 and 6.48 Likert units on a 10 point scale P < 0.001). There was an activation of circadian activity percent at night in the medical food and combination groups while there was no change in parasympathetic activity in either the placebo or trazodone group. These data indicate that Sentra PM can improve the quality of sleep, the response to trazodone as a sleep medication and parasympathetic autonomic nervous system activity.

Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain

Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT2C, 5-HT2A receptors and α1- and α2-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10mg/kg/day) for 2 or 14days. Administration of trazodone for 2 and 14days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT2C receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14days enhanced the tonic activation of postsynaptic α2-adrenoceptors, as indicated by the disinhibitory effect of the α2-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT1A receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT2A agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT2A receptors. The enhancement in α2-adrenergic transmission by trazodone, and its 5-HT2A and 5-HT2C receptor antagonism may contribute to its therapeutic action in major depression.

P.1.c.055 Electrophysiological effects of sustained administration of trazodone on serotonin system

P.1.c.055 Electrophysiological effects of sustained administration of trazodone on serotonin system