Long-term (mean, 8 years) users of benzodiazepines (BZs) were administered a small battery of cognitive tests on three occasions (before BZ taper, and 5 and 12 weeks post taper) as part of their BZ discontinuation program. Ninety-six patients had 5-week and 77 patients had 12-week data. For taper successes, BZ-free status was confirmed by weekly BZ plasma level determinations. Age and education, as well as baseline test scores, were used as covariates for all data analyses. Patients who successfully tapered off BZ were able to complete symbol copying (SC) and digit symbol substitution (DSST) tasks faster than patients still taking BZ (p < 0.05). In addition, using an adjective check list, patients with taper success, i.e., BZ-free patients, reported lower levels of mental and physical sedation and higher levels of tranquilization (p < 0.05) than did patients still taking BZ. These results were confirmed in two multiple regression analyses with SC and DSST as the dependent variables. Higher baseline, younger age, and successful taper status (off BZ) were selected as significant independent predictors of SC and DSST scores. In summary, cognitive functions improved for many long-term BZ users after discontinuing their BZ intake.

Since recent research has suggested that the major metabolites of progesterone are barbiturate-like modulators of GABAergic function, we undertook a pilot study of the efficacy of micronized progesterone in attenuating withdrawal and facilitating discontinuation in benzodiazepine-dependent patients with a minimum of 1 year of continuous daily use. Forty-three patients taking a mean daily dose of 16.2 mg of diazepam (or its equivalent) were assigned, doubleblind, to treatment with either placebo (n = 13) or progesterone (n = 30). Progesterone was titrated to a mean daily dose of 1983 mg, and was co-administered for 3 weeks, after which the benzodiazepine was tapered by 25% per week. Progesterone (or placebo) was then continued for 4 weeks before being discontinued. There was no progesterone versus placebo difference in the severity of taper withdrawal. Withdrawal checklist change scores were 17.3 for progesterone and 16.5 for placebo (F 0.63; df 2.31; n.s.), and the Hamilton rating scale for anxiety change scores were 7.8 for progesterone and 6.3 for placebo (F 0.22; df 2.30; n.s.). There was no difference in ability to remain drug-free at 12 weeks post-taper, with 57% of progesterone-treated patients, and 58% of placebo-treated patients having a successful outcome.

One hundred sixty-six patients suffering from major depressive disorders 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 nefazodone dosage regimens provided during the first week of therapy, one group receiving nefazodone 200 mg/day for 7 days, and another group receiving 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 measures included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as well as global improvement, a daily completed sleep questionnaire, and adverse event assessment. A combination of nefazodone with a benzodiazepine (BZ) caused more sedation than nefazodone alone; triazolam, the BZ with the shortest half-life and the highest dependence on the cytochrome 450 system for its metabolism, caused the least amount of sedation, and alprazolam and diazepam, the two daytime benzodiazepines, caused the most sedation. Triazolam caused significant and identical reduction of insomnia in both nefazodone groups. Compared with nefazodone 200 mg given as monotherapy, insomnia was significantly improved--not only by triazolam, but also alprazolam and diazepam, but not temazepam. The addition of nefazodone raised triazolam plasma levels to almost 500%, the plasma level of desmethyl-diazepam 87%, and that of alprazolam 34%. Temazepam plasma levels remained unchanged. When prescribing nefazodone with a benzodiazepine, one should expect an improved sleep pattern initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytochrome mechanism for metabolism, should be the least sedating, and triazolam, because of its cytochromic metabolism interference with nefazodone should be the most sedating, could not be confirmed. In fact, triazolam 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.