Warren G. Case

Gepirone in anxiety: a pilot study.

Ten patients suffering from generalized anxiety disorder were treated, after a single-blind placebo washout week, with the nonbenzodiazepine anxiolytic gepirone in a 6-week open label trial. Mean Hamilton Anxiety scores improved from 24.8 to 7.1 (p < 0.01). Other physician- and patient-rated scales showed comparable improvement on a mean maximal dose of 41 mg of gepirone. The medication appeared to be nonsedating and well tolerated. The anxiolytic effect of the medication was very marked in several cases, and gepirone appears to have promise as an anxiolytic agent.

Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome

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, double-blind, 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.

Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation.

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.

Doxepin and diazepam in general practice and hospital clinic neurotic patients: A collaborative controlled study

SummaryDoxepin and diazepam were evaluated for therapeutic effectiveness in a double blind study carried out with 69 primarily anxious neurotic outpatients attending either a municipal hospital clinic or a general practitioners office.Doxepin produced more clinical improvement than diazepam in several questionnaire clusters measuring depressive symptomatology, but not in clusters measuring anxious symptomatology.According to several outcome criteria, doxepin tended to produce more clinical improvement in general practice than in clinic patients, while diazepam produced either equal improvement in both populations or slightly more improvement in the clinic.Possibly contributing to the present results are low daily dosage of diazepam, differential pharmacological drug effects, population differences in levels of anxiety and depression, and differences in population characteristics, primarily as related to social class.

Nefazodone in major depression : Adjunctive benzodiazepine therapy and tolerability

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.

Hydroxyzine and chlordiazepoxide in anxious neurotic outpatients: A collaborative controlled study

Abstract Hydroxyzine, in a higher than usual daily dosage (400 mg./day), was compared to chlordiazepoxide and placebo in a double-blind study conducted with 61 clinic and 69 general practice anxious neurotic outpatients. In contrast to studies in which hydroxyzine was administered in dosages of 150–200 mg./day, the present study demonstrated a significant superiority of hydroxyzine over placebo. According to many criterion measures, hydroxyzine appeared as effective as chlordiazepoxide in the symptomatic treatment of neurotic anxiety. The finding that largest drug-placebo differences occurred in middle class general practice patients, as opposed to lower social class clinic patients, and in patients of moderate to severe anxiety rather than in patients who were only mildly ill, has important implications for the selection of appropriate study populations for clinical trials of anti-anxiety agents. The differential dropout rates and differential reporting of side effects observed in the present study clearly favored chlordiazepoxide over hydroxyzine. The presence of disturbing side effects was the most important factor in the moderately high attrition rate (31% for hydroxyzine patients and 25% for chlordiazepoxide patients), and hydroxyzine patients reported significantly more side effects than either chlordiazepoxide or placebo patients at both the 2- and 4-week study periods. These findings would seem to indicate the need for further research to determine whether a dosage can be found at which hydroxyzine produces significantly more clinical improvement than placebo without causing the relatively large number of side effects observed in the present study.

Prazepam in anxiety: A controlled clinical trial

Abstract Prazepam, a benzodiazepine derivative similar in chemical structure and biological activity to diazepam and chlordiazepoxide, has been reported in the literature to possess antianxiety properties in daily doses of up to 80 mg/day. Shaffer et al. 1 found 40–80 mg/day prazepam more effective than placebo but not chlordiazepoxide, in relief of postwithdrawal anxiety in alcoholics. Studies with anxious outpatient psychoneurotics have shown prazepam to be more effective than placebo and equally effective to chlordiazepoxide. For example Silver et al. 2 found prazepam 30–60 mg superior to chlordiazepoxide and placebo in overall efficacy at 4 weeks but not at 2 weeks, while Dunlop and Weisberg 3 reported similar results with 30–60 mg at an endpoint of 4 or 6 weeks. The present 4 week double-blind study was undertaken to help determine the optimum daily dosage of prazepam. To this end the study was designed not only to test the efficacy of 2 daily dosage regimens of prazepam, i.e., 40 and 60 mg, but also to make use of its relatively long half-life by administering it once daily at bedtime.

Doxepin and amitriptyline-perphenazine in mixed anxious-depressed neurotic outpatients: A collaborative controlled study

Doxepin was compared to the combination of amitriptyline-perphenazine in a double-blind controlled study conducted with 100 clinic, general practice, and private psychiatric practice outpatients diagnosed as suffering from a mixed anxiety-depressive reaction. The relatively few statistically significant differences found in the study indicated amitriptyline-perphenazine to be more effective than doxepin (main drug effects), general practice patients to improve the most and private psychiatric patients the least (main population effects), and clinic patients to respond better to doxepin, while general practice and private psychiatric patients improved most with the drug combination (drug×population interaction effects).Amitriptyline-perphenazine was found to produce more improvement in high and doxepin in low depressed patients, and doxepin was observed to be more effective in lower than in higher social class patients. Patients on doxepin tended to report more side effects, but to drop out less frequently than patients on the drug combination.

The uncontrolled case report: a double-edged sword

The advantages and disadvantages of uncontrolled case reports are reviewed using two cases of false-positive reactions to drugs as illustrative examples.