Research and Clinical Trials on Nefazodone (Serzone, Dutonin)

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By Dr Greg Mulhauser

This list of current clinical research trials on Nefazodone (Serzone, Dutonin) is followed by a short set of abstracts from the most recent research articles published on the drug.

Article Contents

Nefazodone (Serzone, Dutonin) Clinical Research Trials

From our searchable database at ClinicalTrialsFeeds.org, this list includes all the latest information about clinical trials involving Nefazodone (Serzone, Dutonin).

 

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Current Research Literature on Nefazodone (Serzone, Dutonin)

Here are abstracts for some of the latest research articles to have appeared on Nefazodone (Serzone, Dutonin):

Can drug safety be predicted and animal experiments reduced by using isolated mitochondrial fractions?

Altern Lab Anim. 2009 Sep; 37(4): 355-65
Pereira SP, Pereira GC, Moreno AJ, Oliveira PJ
Mitochondrial toxicity has resulted in the withdrawal of several drugs from the market. One particular example is nefazodone, an anti-depressant withdrawn in the USA due to hepatoxicity caused by drug-induced mitochondrial dysfunction. Drug development and safety testing can involve the use of large numbers of laboratory animals, which, without a decisive pre-screening for mitochondrial toxicity, are often unable to pre-empt higher mortality rates in some patient groups. The use of isolated mitochondria as a screening tool for drug safety can decrease the number of laboratory animals used in pre-clinical studies, thus improving animal welfare and healthcare outcomes and costs. Novel techniques involving highthroughput methods can be used to investigate whether a molecule is a mitochondrial toxicant. Moreover, these screens are mechanistically-based, since the effects of the drug on oxidative phosphorylation, calcium homeostasis and mitochondrial genetics can be assessed. This review is intended to demonstrate that isolated mitochondrial fractions are suitable for predicting drug and general chemical safety in toxicological screenings, thus contributing to the refinement and reduction of animal use in laboratory research.

Association between the use of serotonin receptor 2A-blocking antidepressants and joint disorders.

Arthritis Rheum. 2009 Oct 15; 61(10): 1322-7
Kling A, Danell-Boman M, Stenlund H, Dahlqvist R
OBJECTIVE: There are case reports about antidepressants causing arthritis and arthralgia, and the majority of these reports deal with atypical antidepressants, which are serotonin receptor 2A (5-HT(2A))-blocking substances. The aim of this study was to examine a possible association between joint disorders and the use of 5-HT(2A)-blocking atypical antidepressants. METHODS: We performed a retrospective study using reports of adverse drug reactions (ADRs) of 5-HT(2A)-blocking atypical antidepressant substances concerning joint disorders reported to the Swedish Adverse Drug Reactions Committee and the World Health Organization (WHO) Adverse Reactions Database during the period January 1, 1990 to December 31, 2006. The reports of joint disorders were related to sales figures measured as defined daily doses and to the total number of ADR reports. RESULTS: In the Swedish material, the 5-HT(2A) antagonists were 45 times more often reported to give joint ADRs when related to sales figures and compared with the selective serotonin reuptake inhibitors (SSRIs; P < 0.001). Joint disorders constituted 6.6% of the total number of reports of possible ADRs for the three 5-HT(2A)-blocking substances mianserin, mirtazapine, and nefazodone compared with 0.5% for the SSRIs (P < 0.001). In the WHO material, the joint disorders constituted 1.3% of all ADRs for the 5-HT(2A)-blocking antidepressants and 0.6% for the SSRIs (P < 0.001). CONCLUSION: In this study, joint disorders were considerably more frequently reported ADRs of 5-HT(2A)-blocking antidepressants than of other comparable drugs, suggesting a possible association between the use of 5-HT(2A)-blocking antidepressants and joint disorders.

Treatment of sleep dysfunction and psychiatric disorders.

Curr Treat Options Neurol. 2009 Sep; 11(5): 349-57
Becker PM, Sattar M
Patients with neurologic disorders commonly experience sleep dysfunction and psychiatric disorders. The most common sleep dysfunction is insomnia, which is a primary symptom in 30% to 90% of psychiatric disorders. Insomnia and fatigue are prominent symptoms of anxiety disorders and major depression that may occur in patients who are treated but have residual sleep dysfunction. Anxiety and depressive disorders account for 40% to 50% of all cases of chronic insomnia. It is also recognized that primary insomnia and other primary sleep disorders produce symptoms that are similar to those reported by patients with psychiatric disorders. A clinician must judge whether sleep deprivation causes mood disturbance or whether depressive or anxiety disorder represents the primary reason for sleep dysfunction. When insomnia is comorbid with mild to moderate depression, therapy should begin with bedtime dosing of sedating antidepressants such as mirtazapine, nefazodone, or tricyclic antidepressants, which are preferred because of their sedative effects. Often side effects limit their usefulness. Intervention for chronic insomnia is similar in nonpsychiatric and psychiatric patients. Behavioral therapies, particularly multicomponent cognitive-behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia. The most studied pharmacologic agents to treat insomnia are sedative hypnotic agents, particularly those that are active through the benzodiazepine receptor-GABA (gamma-aminobutyric acid) complex, such as benzodiazepines, eszopiclone, zaleplon, and zolpidem. Melatonin and the melatonin-receptor agonist ramelteon have not had adequate study in psychiatric patients to define their use, but small studies suggest benefit. Prescription of adjunctive trazodone (50-150 mg) is a common clinical practice to treat comorbid insomnia during antidepressant therapy, but published data are surprisingly limited, considering its frequent use. Although there has been insufficient research on the use of atypical antipsychotic agents in severe insomnia, psychiatrists use quetiapine, olanzapine, or others to lessen agitation that disrupts sleep. When insomnia or hypersomnia continue even as mood, anxiety, or thought disorders improve with standard therapy, the physician should consider the potential presence of underlying sleep disorders.

A proposal for a pharmacokinetic interaction significance classification system (PISCS) based on predicted drug exposure changes and its potential application to alert classifications in product labelling.

Clin Pharmacokinet. 2009; 48(10): 653-66
Hisaka A, Kusama M, Ohno Y, Sugiyama Y, Suzuki H
BACKGROUND AND OBJECTIVE: Pharmacokinetic drug-drug interactions (DDIs) are one of the major causes of adverse events in pharmacotherapy, and systematic prediction of the clinical relevance of DDIs is an issue of significant clinical importance. In a previous study, total exposure changes of many substrate drugs of cytochrome P450 (CYP) 3A4 caused by coadministration of inhibitor drugs were successfully predicted by using in vivo information. In order to exploit these predictions in daily pharmacotherapy, the clinical significance of the pharmacokinetic changes needs to be carefully evaluated. The aim of the present study was to construct a pharmacokinetic interaction significance classification system (PISCS) in which the clinical significance of DDIs was considered with pharmacokinetic changes in a systematic manner. Furthermore, the classifications proposed by PISCS were compared in a detailed manner with current alert classifications in the product labelling or the summary of product characteristics used in Japan, the US and the UK. METHODS: A matrix table was composed by stratifying two basic parameters of the prediction: the contribution ratio of CYP3A4 to the oral clearance of substrates (CR), and the inhibition ratio of inhibitors (IR). The total exposure increase was estimated for each cell in the table by associating CR and IR values, and the cells were categorized into nine zones according to the magnitude of the exposure increase. Then, correspondences between the DDI significance and the zones were determined for each drug group considering the observed exposure changes and the current classification in the product labelling. Substrate drugs of CYP3A4 selected from three therapeutic groups, i.e. HMG-CoA reductase inhibitors (statins), calcium-channel antagonists/blockers (CCBs) and benzodiazepines (BZPs), were analysed as representative examples. The product labelling descriptions of drugs in Japan, US and UK were obtained from the websites of each regulatory body. RESULTS: Among 220 combinations of drugs investigated, estimated exposure changes were more than 5-fold for 41 combinations in which ten combinations were not alerted in the product labelling at least in one country; these involved buspirone, nisoldipine and felodipine as substrates, and ketoconazole, voriconazole, telithromycin, clarithromycin and nefazodone as inhibitors. For those drug combinations, the alert classifications were anticipated as potentially inappropriate. In the current product labelling, many inter-country differences were also noted. Considering the relationships between previously observed exposure changes and the current alert classifications, the boundaries between 'contraindication' and 'warning/caution' were determined as a 7-fold exposure increase for statins and CCBs, and as a 4-fold increase for BZPs. PISCS clearly discriminated these drug combinations in accordance with the determined boundaries. Classifications by PISCS were expected to be valid even for future drugs because the classifications were made by zones, not by designating individual drugs. CONCLUSION: The present analysis suggested that many current alert classifications were potentially inappropriate especially for drug combinations where pharmacokinetics had not been evaluated. It is expected that PISCS would contribute to constructing a leak-less alerting system for a broad range of pharmacokinetic DDIs. Further validation of PISCS is required in clinical studies with key drug combinations, and its extension to other CYP and metabolizing enzymes remains to be achieved.

Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins.

Drug Metab Dispos. 2009 Aug 31;
Usui T, Mise M, Hashizume T, Yabuki M, Komuro S
Prediction of idiosyncratic drug-induced liver injury (DILI) is difficult and the underlying mechanisms are not fully understood. However, many drugs causing DILI are considered to form reactive metabolites and covalently bind to cellular macromolecules in the liver. The objective of this study was to clarify whether the risk of idiosyncratic DILI can be estimated by comparing in vitro covalent binding (CB) levels among 12 positive compounds (acetaminophen, alpidem, bromfenac, carbamazepine, diclofenac, flutamide, imipramine, nefazodone, tacrine, ticlopidine, tienilic acid, troglitazone) for DILI and 12 negative compounds (acetylsalicylic acid, caffeine, dexamethasone, losartan, ibuprofen, paroxetin, pioglitazone, rosiglitazone, sertraline, theophylline, venlafaxine, zolpidem). After incubation with human liver microsomes in the presence of NADPH, there was a large overlap in the distribution of CB amounts between the positive and negative groups. On addition of UDP glucuronic acid (UDPGA) as a cofactor for glucuronidation, the CB levels of bromfenac and diclofenac were increased. With addition of nucleophilic GSH, values for most compounds were decreased. However, separation of the two groups on the basis of CB could not be improved by UDPGA or GSH. Furthermore, CB with human hepatocytes also failed to discriminate positive from negative compounds. Therefore, the CB amount alone is not sufficient for risk assessment of DILI. In contrast, when the CB amount was multiplied by the maximum daily dose, which may reflect maximum hepatic exposure, the two groups did become discriminated. Taken together, our findings suggest that the combination of CB amount and daily dose can estimate the risk of idiosyncratic DILI.

 

This page was last reviewed by Dr Greg Mulhauser, Monday, 1 June 2009.

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