Nefazodone adverse effects

Trazodone routinely causes sedation, which is why it is used far more often as an adjunct with other antidepressants for sleep than as a primary agent for the treatment of depression. Priapism is a rare but serious adverse effect in males who take trazodone. In addition, orthostatic hypotension and dizziness are more common with trazodone than with nefazodone because the latter agent has a weaker effect at a-adrenergic receptors and also has a balancing of adrenergic effects owing... 

Nefazodone is generally well tolerated. It has been shown to improve sleep architecture (Armitage et ah, 1994), and has minimal associated sexual dysfunction. The adverse effects associated with nefazodone, in descending order of frequency, are dry mouth, somnolence, dizziness, nausea, constipation, blurred vision, and postural hypotension (Preskorn, 1993). Nefazodone does not slow cardiac conduction therefore, it has been tolerated in intentional overdoses of up to 11,200 mg. 

Adverse effects. Side effects that occurred with nefazodone to a greater degree than with placebo and that were dose related included somnolence, dry mouth, nausea, and dizziness. Furthermore, there is no need to taper the dose if discontinuation is being considered (L. Friedman et al. 1992 L. H. Gold and Balster 1991]. More than 2,256 patients have been studied in clinical trials, and, to date, only two cases of overdose (>3,600 mg ingested] have been reported both patients recovered with no sequelae. 

TABLE 7-25. Comparison of the placebo-adjusted incidence rate (%) of frequent adverse effects for fluoxetine, sertraline, paroxetine, venlafaxine, and nefazodone... 

TABLE 7-26. Placebo-adjusted, dose-dependent adverse effects of paroxetine, venlafaxine, and nefazodone (mg/d)... 

In the analysis of the comparative adverse effects of the newer generation of antidepressants, dizziness was most common with nefazodone. Indeed, it occurred more often on this drug than with any of the others (1). These results are compatible with its preclinical pharmacology, which differs substantially from the other new antidepressants (i.e., most potent action is blockade of the 5-HT2a receptor). 

In comparison with the other new antidepressants, the incidence rate of the following adverse effects was appreciably lower on nefazodone ... 

The adverse effects of SSRIs, venlafaxine, and nefazodone in children and adolescents are comparable with those in adults (see Chapter 7) and have been documented in both clinical trials and practice ( 35, 36, 119, 120 and 121 123). As in adults, isolated case reports have described behavioral activation in children and adolescents given SSRIs (133, 134). The significance of such reports in terms of a causal link to the drug is difficult because of their rare and anecdotal nature and because the patients are at increased risk for such behavioral disturbances relative to the general population as a result of their underlying psychiatric disorder. 

Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse effects of many 3A4-dependent drugs. For example, triazolam levels are increased by concurrent administration of nefazodone such that a reduction in triazolam dosage by 75% is recommended. Likewise, administration of nefazodone with simvastatin has been associated with 20-fold increase in plasma levels of simvastatin. 

There are many other ways in which SSRIs can interfere with sexual function, for example by causing loss of sexual interest and erectile difficulties. In an open, prospective study of 1000 Spanish patients taking a variety of antidepressants, there was an overall incidence of sexual dysfunction of 59% (15). The highest rates, 60-70%, were found with SSRIs (including fluvoxamine) and venlafax-ine. The lowest rates were found with mirtazepine (24%), nefazodone (8%), and moclobemide (4%). Spontaneous resolution of this adverse effect was uncommon - 80% of subjects had no improvement in sexual function over 6 months of treatment. 

Sexual adverse effects seem to occur less often with nefazodone than with SSRIs (SEDA 20, 9). 

Schrader GD, Roberts-Thompson IC. Adverse effect of nefazodone hepatitis. Med J Aust 1999 170(9) 452. 

In 12 healthy volunteers, there were no clinically significant alterations in blood concentrations of lithium or nefazodone and its metabolites when the drugs were coadministered (587). The addition of lithium for 6 weeks to nefazodone in 14 treatment-resistant patients produced no serious adverse effects and no dropouts (588). Lithium augmentation of nefazodone in 13 treatment-resistant depressed patients was associated with a variety of annoying adverse effects, but none led to treatment withdrawal (589). 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Khouzam FIR. The antidepressant nefazodone. A review of its pharmacology, clinical efficacy, adverse effects, dosage, and administration. Journal of Psychosocial Nursing and Mental Flealth Services 2000 38 20-25. 

Potential interactions through the cytochrome P450 CYP 2D6 and CYP 3A4 enz)unes can be noted from Tables 19.2a and 19.2b. The combination of drugs that are substrates of the same enzyme creates potential for competitive inhibition of their metabolism with unexpected elevation of plasma concentration. Similarly, potent inhibitors, e.g. fluoxetine and paroxetine (CYP 2D6), fluoxetine and nefazodone (CYP 3A4) and fluvoxamine (CYP 1A2), may cause adverse effects by reducing metabolic breakdown of co-prescribed drugs that are used in standard doses. Antidepressants are commonly prescribed with antipsychotics in a depressive... 

The use of cisapride and its benefit to harm balance in children has been reviewed (25). Overall it is well tolerated. The most common adverse effects are diarrhea, abdominal cramps, borborygmi, and colic. Serious adverse events are rare and include isolated cases of extrapyramidal reactions, seizures in epileptic patients, cholestasis, QT interval prolongation and ventricular dysrhythmias, anorexia, and enuresis. Interactions of cisapride with other drugs are similar to those reported in adults. Co-administration of drugs that inhibit CYP3A4, such as imidazoles, macrolide antibiotics, the antidepressant nefazodone, and protease inhibitors such as ritonavir, are contraindicated. Furthermore, co-administration of anticholinergic drugs can compromise the beneficial effects of cisapride. 

Gastrointestinal adverse effects of naltrexone were also observed in 183 alcohol-dependent individuals who received either naltrexone or nefazodone (15). These adverse effects predicated early termination of naltrexone used to treat alcohol dependence (16). 

Reboxetine is metabolized by CYP3A4. In 11 healthy volunteers ketoconazole, an inhibitor of CYP3A4, increased the plasma AUC of reboxetine by about 50% and prolonged the half-life (5). The adverse effects profile of reboxetine was not altered by ketoconazole, but the finding suggests that reboxetine should be used with caution in combination with drugs that inhibit CYP3A4, for example nefazodone and fluvoxamine. 

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