The comparative efficacy of trazodone and imipramine in the treatment of depression. (9/51)

OBJECTIVE: To review published clinical trials comparing the efficacy of trazodone with that of tricyclic antidepressant medication. DATA SOURCES: MEDLINE was searched for relevant articles published from 1983 to 1991. The bibliography of a review article was searched for further references. STUDY SELECTION: In all, 25 clinical trials were found. Six of these met the methodologic assessment criteria (adapted from the McMaster guidelines for the evaluation of clinical trials), which included the stipulation of a score of 18 or more on the Hamilton depression rating scale and a 50% reduction in that score as an outcome measure. DATA EXTRACTION: All six studies compared trazodone with imipramine. Data describing response to the treatments were extracted, and post-hoc power estimates were calculated. The analysis also involved statistical tests of a modified null hypothesis, the generation of confidence intervals (CIs) and a meta-analysis. DATA SYNTHESIS: All the studies found no significant difference in the efficacy of trazodone and imipramine. However, the statistical power of most of them was less than 50% and often less than 10%; thus there was a low probability that differences would be detected. The results of statistical tests of the modified null hypothesis, inspection of the CIs and the results of the meta-analysis all suggested that trazodone, and imipramine are equally efficacious. CONCLUSION: The application of various techniques for the analysis of equivalence data suggests that trazodone and imipramine are of approximately equivalent efficacy. The data are compatible with small differences in efficacy, but the differences are of a magnitude such that they are unlikely to be of clinical significance.  (+info)

Investigation of a fatality due to trazodone poisoning: case report and literature review. (10/51)

Trazodone is an antidepressant agent used in Spain since 1975. There are few documented reports of fatalities solely attributed to trazodone and none in which the main metabolite is analyzed. A fatal case of self-poisoning following oral ingestion is reported along with a description of the validated analytical methods involved, a discussion of poisoning characteristics, and a review of reports describing trazodone overdose cases with analytical results. The deceased was an 86-year-old man with cancer, who suffered depression. He went to see his doctor in a primary health care unit and told him he had just taken an unknown amount of tablets of Deprax to commit suicide. The doctor induced emesis as a first emergency measure. His death occurred before arriving to the hospital, and he left a suicide note nearby. Systematic toxicological analysis of postmortem blood used routinely in our laboratory revealed the presence of trazodone 4.9 mg/L and m-chlorophenyl-piperazine (m-CPP) 0.6 mg/L, its active and major metabolite. In addition, metamizol 19.6 mg/L and 4-methyl-amino-antipyrine (4-MAA) 40.7 mg/L, its active metabolite, were also found in blood. All drugs and metabolites involved in the case were detected using gas chromatography-nitrogen-phosphorus detection (GC-NPD) and confirmed using gas chromatography-mass spectrometry (GC-MS) mode total ion chromatogram. An additional high-performance liquid chromatography-diode array detection (HPLC-DAD) screening also obtained the same results. Quantitation of trazodone together with its metabolite in blood was carried out using GC-NPD, while quantitation of metamizol was performed using HPLC-DAD. Limits of detection for trazodone and m-CPP were 33 and 11 microg/L, respectively, absolute recoveries were more than 86% and 75%, respectively, intra-assay precisions less than 4%, interassay precisions less than 5%, and linearity up to 2.0 mg/L. Limit of detection for metamizol was 1117 microg/L, absolute recovery more than 84%, intra-assay precision less than 8%, interassay precision less than 12%, and linearity up to 48 mg/L. Based on the autopsy findings, patient history, toxicology results, and previously reported trazodone intoxications, the forensic pathologists ruled that the cause of death was due to an overdose of trazodone, and the manner of death was listed as suicide.  (+info)

Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. (11/51)

Treatment with the antidepressant nefazodone has been associated with clinical idiosyncratic hepatotoxicty. Using membranes expressing human bile salt export pump (BSEP), human sandwich hepatocytes, and intact rats, we compared nefazodone and its marketed analogs, buspirone and trazodone. We found that nefazodone caused a strong inhibition of BSEP (IC(50) = 9 microM), inhibition of taurocholate efflux in human hepatocytes (IC(50) = 14 microM), and a transient increase in rat serum bile acids 1 h after oral drug administration. Buspirone or trazodone had no effect on biliary transport system. Nefazodone produced time- and concentration-dependent toxicity in human hepatocytes with IC(50) = 18 microM and 30 microM measured by inhibition of protein synthesis after 6 h and 24 h incubation, respectively. Toxicity was correlated with the amount of unmetabolized nefazodone. Partial recovery in toxicity by 24 h has been associated with metabolism of nefazodone to sulfate and glucuronide conjugates. The saturation of nefazodone metabolism resulted in sustained decrease in protein synthesis and cell death at 50 microM. The toxicity was not observed with buspirone or trazodone. Addition of 1-aminobenzotriazole (ABT), an inhibitor of CYP450, resulted in enhancement of nefazodone toxicity at 10 microM and was associated with accumulation of unmetabolized nefazodone. In human liver microsomes, ABT also prevented metabolism of nefazodone and formation of glutathione conjugates. We suggest that inhibition of bile acid transport by nefazodone is an indicator of potential hepatotoxicity. Our findings are consistent with the clinical experience and suggest that described methodology can be applied in the selection of nonhepatotoxic drug candidates.  (+info)

Sensitive extractive spectrophotometric methods for the determination of trazodone hydrochloride in pharmaceutical formulations. (12/51)

Two simple, rapid and sensitive extractive spectrophotometric methods have been developed for the assay of trazodone hydrochloride (TRH) in pure and pharmaceutical formulations. These methods are based on the formation of chloroform soluble ion-association complexes of TRH with bromothymol blue (BTB) and with bromocresol purple (BCP) in KCl-HCl buffer of pH 2.0 (for BTB) and in NaOAc-AcOH buffer of pH of 3.6 (for BCP) with absorption maximum at 423 nm and at 408 nm for BTB and BCP, respectively. Reaction conditions were optimized to obtain the maximum color intensity. The absorbance was found to increase linearly with increase in concentration of TRH, which was corroborated by the calculated correlation coefficient values (0.9996, 0.9945). The systems obeyed Beer's law in the range of 0.2-14.5 and 0.2-14.1 microg/ml for BTB and BCP, respectively. Various analytical parameters have been evaluated and the results have been validated by statistical data. No interference was observed from common excipients present in pharmaceutical formulations. The proposed methods are simple, accurate and suitable for quality control applications.  (+info)

Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine. (13/51)

Paroxetine is commonly used as a selective serotonin reuptake inhibitor for the treatment of depression and other psychiatric disorders. However, the molecular mechanisms of the paroxetine effects have not yet been sufficiently clarified. Using Xenopus oocyte expression assays, we investigated the effects of paroxetine on G protein-activated inwardly rectifying K+ (GIRK) channels, which play an important role in reducing neuronal excitability in most brain regions and the heart rate. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, paroxetine reversibly reduced inward currents through the expressed GIRK channels. The inhibition was concentration-dependent, but voltage-independent and time-independent during each voltage pulse. However, two structurally different antidepressants: milnacipran and trazodone, caused only a small inhibition of basal GIRK currents. Additionally, Kir1.1 and Kir2.1 channels were insensitive to all of the antidepressants. Furthermore, the GIRK currents induced by activation of A1 adenosine receptors or by ethanol were inhibited by extracellularly applied paroxetine in a concentration-dependent manner, but not affected by intracellularly applied paroxetine. Our results suggest that inhibition of GIRK channels by paroxetine may contribute partly to some of its therapeutic effects and adverse side effects.  (+info)

Effect of penetration enhancers on skin permeation of trazodone hydrochloride from matrix type transdermal formulation through mouse and human cadaver epidermis. (14/51)

A transdermal dosage form of trazodone hydrochloride (TZN) may be useful in the treatment of moderate to severe depression in schizophrenic patients by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of TZN would attenuate fluctuating plasma level of TZN resulting from oral therapy. The aim of the current investigation was to evaluate its flux and the effects of various penetration enhancers, viz., isopropyl myristate (IPM), isopropyl palmitate (IPP), butanol and octanol on transdermal permeation from matrix-based formulations through the skin. The enhancing effect on the permeation of TZN was determined using the mouse and human cadaver epidermis. In vitro permeation data were collected at 37 degrees C using Keshary-Chien diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation flux of TZN, enhancement ratio and the diffusion parameter. The highest enhancing effect was obtained with IPM followed by butanol, octanol and IPP. In general, higher fluxes were observed through mouse epidermis as compared with the human cadaver epidermis. The skin retention of TZN for both the species in the presence of different enhancers was nearly 3 times higher than for the control formulation. Based on the observed results, a transdermal patch of about 70 cm2 consisting of 10 % IPM should be able to attain and maintain therapeutic plasma concentration of TZN at 0.75 mg/mL over a period of 24 h.  (+info)

Tinnitus treatment with Trazodone. (15/51)

Tinnitus is a common symptom, defined as a sound perception in absence of a sound stimulus. AIM: Evaluate if Trazodone, an antidepressant drug, which modulates serotonin at central neuronal pathways, is effective in controlling tinnitus. STUDY DESIGN: Prospective, double blind, randomized, placebo-controlled. MATERIALS AND METHODS: Study performed with patients presenting tinnitus. 85 patients were analyzed between February and June of 2005. 43 received trazodone and 42 placebo, for 60 days. The clinical criteria of analysis were tinnitus intensity, discomfort and life quality impact by tinnitus, using an analogue scale varying between 0 and 10, scored by patients before and after drug or placebo use. RESULTS: There was a significant improvement in intensity, discomfort and life quality in both groups after treatment; however, there was no significant difference between the drug and placebo groups. Patients with age equal or over 60 years presented better results after treatment. CONCLUSION: Trazodone was not efficient in controlling tinnitus in the patients evaluated under the doses utilized.  (+info)

Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. (16/51)

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