Disease relevance of C07256

• Nefazodone-induced liver failure: report of three cases [1].
• Nefazodone-induced carbamazepine toxicity [2].
• The related compound, nefazodone, does not cause sexual dysfunction or priapism, but is associated with sedation [3].
• Treatment of chronic fatigue syndrome with nefazodone [4].
• Nefazodone-induced hypoglycemia in a diabetic patient with major depression [5].

Psychiatry related information on C07256

• The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group [6].
• Does psychosocial functioning improve independent of depressive symptoms? A comparison of nefazodone, psychotherapy, and their combination [7].
• Nefazodone significantly increased total REM sleep time [8].
• Nefazodone and akathisia [9].
• Nefazodone treatment for chronic posttraumatic stress disorder: an open trial [10].

High impact information on C07256

• METHODS: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both [6].
• Rhabdomyolysis with simvastatin and nefazodone [11].
• BACKGROUND AND OBJECTIVE: Nefazodone inhibits CYP3A; therefore coadministration with CYP3A substrates such as terfenadine or loratadine may result in increased exposure to these drugs [12].
• Concomitant administration of nefazodone with terfenadine may have predisposed individuals to the arrhythmia associated with QTc prolongation, torsade de pointes, when terfenadine was available for clinical use [12].
• In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep [8].

Chemical compound and disease context of C07256

• OBJECTIVE: To describe three cases of subfulminant liver failure that were probably caused by nefazodone, a new antidepressant that is a synthetically derived phenylpiperazine [1].
• Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep [8].
• Exposure to m-chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state [13].
• Subjects with liver cirrhosis had about a two-fold greater systemic exposure to nefazodone and hydroxynefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state [13].
• The reduction in REM sleep produced by antidepressants may be an important part of their mechanism of action; however, the ability of new antidepressant compounds, such as nefazodone and moclobemide, to increase REM sleep throws doubt on this suggestion [14].

Biological context of C07256

• Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis [13].
• Although nefazodone may interact with some other medications (e.g., increases at steady state in AUC: alprazolam, twofold; triazolam, fourfold), drug-drug interactions involving patients have been clinically minor [15].
• Our knowledge of the isoenzymes involved in the various oxidation pathways and their relevance for potential drug interactions varies from a considerable amount for most of the SSRI and nefazodone, to minimal for reboxetine and tianeptine [16].
• Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20% [17].
• We examined retrospective data from our clinic to investigate whether nefazodone has utility in the treatment of nonparaphilic compulsive sexual behavior [18].

Anatomical context of C07256

• Nefazodone in the breast milk of nursing mothers: a report of two patients [19].
• RESULTS: mCPP and two hydroxylated derivatives were the principal metabolites formed from nefazodone by liver microsomes [20].
• In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls [21].
• Effects of nefazodone on the immune system of mice [22].
• Absorption and presystemic metabolism of nefazodone administered at different regions in the gastrointestinal tract of humans [23].

Associations of C07256 with other chemical compounds

• These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action [8].
• The results of the study demonstrated that the decrease from mean baseline platelet 5-HT after SSRI treatment was significantly greater than the change after nefazodone treatment (-88% vs. -3%; Mann-Whitney U-test, p = 0.0002) [24].
• Randomised controlled study of sleep after nefazodone or paroxetine treatment in out-patients with depression [25].
• A range of effective pharmacotherapeutic strategies are available, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, the 5-HT2 blocker nefazodone, and the serotonin-norepinephrine reuptake inhibitor venlafaxine [26].
• It was later shown to inhibit both serotonin and norepinephrine uptake in vitro, attributes which most likely impart its clinical efficacy and which differentiate nefazodone from its chemical predecessor trazodone [27].

Gene context of C07256

• Nefazodone is metabolised by and inhibits CYP3A4 [17].
• Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2 [17].
• A metabolite of nefazodone, mCPP, is a weak and probably clinically insignificant inhibitor of CYP2D6 [28].
• Fluoxetine, mirtazapine and nefazodone did not change the activity of CYP3A in liver microsomes after their administration to rats [29].
• Other antidepressants, such as nefazodone or mirtazapine, act as direct antagonists of 5-HT2C receptors [30].

Analytical, diagnostic and therapeutic context of C07256

• The effects of a novel antidepressant, nefazodone (50 mg, 100 mg, and 200 mg orally) on neuroendocrine function and temperature were assessed using a single-blind, crossover design in eight healthy male volunteers [31].
• To determine if differences exist among the newer antidepressants, the authors retrospectively analyzed data from clinical trials comparing nefazodone with SSRIs and with imipramine [32].
• Pharmacotherapy consisted of open-label nefazodone, 300-600 mg per day in two divided doses prescribed by psychiatrists [33].
• This double-blind study tested the efficacy of nefazodone versus placebo for the treatment of depression in actively drinking alcohol-dependent patients who were also participating in weekly group treatment for alcoholism [34].
• CONCLUSION: Results from this preliminary retrospective study suggest that nefazodone decreases the frequency of sexual obsessions and compulsions but does not produce the undesired sexual side effects caused by SSRI treatment [18].

References