NEFAZODONE IN MAJOR DEPRESSION - ADJUNCTIVE BENZODIAZEPINE THERAPY AND TOLERABILITY

One hundred sixty-six patients suffering from major depressive disorde rs were treated for 8 weeks with nefazodone in an open study in dosage ranges from 200 to 600 mg. This report focuses primarily on the first week of therapy and on the concomitant use of several benzodiazepines , one of,which is not metabolized by the cytochrome system (temazepam) . Triazolam response was further evaluated as a function of two nefazo done dosage regimens provided during the first week of therapy, one gr oup receiving nefazodone 200 mg/day for 7 days, and another group rece iving nefazodone 200 mg/day for 3 days, followed by 4 days with 400 mg /day. Finally, a comparison of three different nefazodone dosages, the third being 400 mg from day 1 on, was also carried out. Outcome measu res included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as w eb as global improvement, a daily completed sleep questionnaire, and a dverse event assessment. A combination of nefazodone with a benzodiaze pine (BZ) caused more sedation than nefazodone alone; triazolam, the B Z with the shortest half-life and the highest dependence on the cytoch rome 450 system for its metabolism, caused the least amount of sedatio n, and alprazolam and diazepam, the two daytime benzodiazepines, cause d the most sedation. Triazolam caused significant and identical reduct ion of insomnia in both nefazodone groups. Compared with nefazodone 20 0 mg given as monotherapy, insomnia was significantly improved-not onl y by triazolam, but also alprazolam and diazepam, but not temazepam. T he addition of nefazodone raised triazolam plasma levels to almost 500 %, the plasma level of desmethyldiazepam 87%, and that of alprazolam 3 4%. Temazepam plasma levels remained unchanged. When prescribing nefaz odone with a benzodiazepine, one should expect an improved sleep patte rn initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytoc hrome mechanism for metabolism, should be the least sedating, and tria zolam, because of its cytochromic metabolism interference with nefazod one should be the most sedating, could not be confirmed. In fact, tria zolam 0.25 mg capsules seem to be the safest treatment of choice when one has to combine a benzodiazepine with nefazodone in initial stages of therapy, at least of the four benzodiazepines tested in this study.