NEFAZODONE - A NEW ANTIDEPRESSANT

The chemistry, pharmacology, pharmacokinetics, and clinical efficacy o f nefazodone hydrochloride, a new antidepressant, are described. Nefaz odone enhances serotonin (5-hydroxytryptamine [5-HT]) synaptic transmi ssion by acting as an antagonist at 5-HT2 receptors and by inhibiting the reuptake of 5-HT. These two mechanisms combined may enhance 5-HT1A -mediated transmission. In addition, nefazodone weakly inhibits the re uptake of norepinephrine. Nefazodone is a structural analogue of trazo done but is pharmacologically distinct. In placebo-controlled trials, nefazodone was as effective as imipramine for the treatment of major d epression and produced clinical benefits in patients with depression-r elated anxiety and sleep disturbances. More than 2000 patients have re ceived nefazodone in clinical trials. The most commonly reported adver se drug reactions (ADRs) are asthenia, somnolence, dry mouth, nausea, constipation, dizziness, lightheadedness, confusion, abnormal vision, and blurred vision. The incidence of sexual-dysfunction ADRs may be le ss than that reported for other antidepressants. Nefazodone does not i nhibit rapid-eye movement sleep. Nefazodone, an inhibitor of the hepat ic P-450 isoenzyme CYP3A4, may increase concentrations of drugs metabo lized by this isoenzyme, such as terfenadine, astemizole, triazolam, a lprazolam, and midazolam. Caution should be exercised in administering nefazodone hydrochloride with triazolobenzodiazepines, and coadminist ration with terfenadine or astemizole is contraindicated. The dosage s hould start at 100 mg twice daily and then be increased, depending on occurrence of ADRs and the patient's clinical response, to 300-600 mg daily. In elderly or debilitated patients, the initial dosage should b e half the usual dosage. Nefazodone hydrochloride is as effective as o ther available antidepressants and may cause fewer ADRs.