Nefazodone in Major Depression

Abstract

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.

The effect of personality on withdrawal severity and taper outcome in benzodiazepine dependent patients

“…These patients often continue to take their BZ for years, at least in part to avoid withdrawal symptoms. Previously published studies have found clinically significant levels of anxious and depressive symptomatology in these patients (Rickels et al 1990) despite seemingly adequate BZ dosing. This implies that some patients may be bound to a treatment that only partly relieves their symptoms.…”

“…There is significant variability among patients, however, in the severity of the BZ withdrawal syndrome as well as the ability to maintain a BZ-free state after discontinuation. Previous research by this group and others (Tyrer et al 1983 ;Rickels et al 1990 ;Schweizer et al 1990) has demonstrated that gradual, as opposed to abrupt, taper of BZ medications is better tolerated and results in a significantly higher success rate for discontinuation. Yet even with gradual taper, there remains a group of patients that are unable to tolerate BZ discontinuation.…”

Personality and symptom sensitivity predictors of alprazolam withdrawal in panic disorder

“…'relapse' or 'rebound anxiety '), although the presence of certain withdrawal-specific anxiety symptoms (e.g. perceptual distortions, de-realization, nausea) (Schopf, 1983 ;Tyrer et al 1983 ;Busto et al 1986) and a characteristic time course of onset and offset (Busto et al 1986;Rickels et al 1990), may sometimes help. Nonetheless, no scale used to measure BZ discontinuation symptom severity can entirely overcome this confounding of withdrawal and re-emergent anxiety symptoms.…”

“…The significant variability among patients in the severity of withdrawal has been associated with both drug treatment and patient factors. Drug treatment factors found to be important have included BZ dose (Rickels et al 1988), potency (Tyrer, 1988) and half-life (Fontaine et al 1984 ;Rickels et al 1986;Roy-Byrne et al 1989), duration of treatment (Rickels et al 1983) and rate or speed of taper/discontinuation (Roy-Byrne et al 1989 ;Rickels et al 1990 ;Schweizer et al 1990). Patient factors have included type of diagnosis (e.g.…”

“…Patient factors have included type of diagnosis (e.g. withdrawal is worse in panic disorder than generalized anxiety disorder (GAD)) (Klein et al 1994), severity of the underlying anxiety syndrome and certain personality features, including dependence, neuroticism and harm avoidance (Tyrer et al 1983 ;Rickels et al 1988Rickels et al , 1990Schweizer et al 1990.…”