Within the framework of a large-scale clinical study on the effect of diazepam in chronic anxiety, diazepam (D) and desmethyldiazepam (DD) plasma concentrations were determined frequently. Significant relationships were found between the clinical effect and the plasma concentrations of D and DD, respectively; a curvilinear relationship resulted if the dosage was disregarded, but within the individual dosage groups the relationship was found to be linear. For these computations, the daily diazepam dose was treated as a covariable in a factorial analysis of variance approach. It was found, in addition, that the daily diazepam dose was one of the most significant predictors of the plasma concentration of D or DD, respectively. The steady state plasma concentrations were highest in patients experiencing an exacerbation of their conditions of anxiety if they were returned to placebo after 14 to 22 weeks of diazepam medication. The lowest steady state concentrations were found with those patients who showed withdrawal symptoms under these conditions.

A multiple step-search regression procedure was applied to data obtained with 37 diazepam and 42 halazepam treated anxious outpatients. Good treatment outcome was predicted for those patients who reported a more adequate family adjustment, the presence of precipitating stress, and who either had no prior psychotropic drug treatment, or if they had received such treatment, had experienced a good response. Probably of greatest interest to the practicing clinician was the observation that patients high in initial anxiety but low in initial interpersonal problems improved the most with both medications. Differential drug effects indicated halazepam to do particularly poorly in less anxious patients and in those patients given a good prognosis by the doctor. Diazepam response was much less affected by these variables. It is speculated that the excessive sedating effect of the daily halazepam dosage (160 mg/d) used in this study may explain these differential drug effects. In the dosages employed, namely, diazepam 20 mg/d and halazepam 160 mg/d, diazepam produced the more consistent anti-anxiety effects. The indication that halazepam 160 mg/d was more effective than diazepam 20 mg/d in the initially sicker patients, while of interest, is probably simply a dose-related phenomenon, indicating that diazepam 20 mg/d was too low a daily dosage for severely anxious patients, a fact well known by most clinicians.

A multiple regression analysis conducted with 125 anxious outpatients has indicated chlordiazepoxide (40 mg/day) to produce more improvement than hydroxyzine (400 mg/day); and patients from general practice, with better prognoses, and with higher initial anxiety to do better, irrespective of treatment agent, than patients from clinics, with poor prognoses, and with low initial anxiety. Furthermore, the analysis indicated chlordiazepoxide to produce more improvement than hydroxyzine in more chronically ill, more liked, and employed patients, while hydroxyzine was especially effective in less liked and unemployed patients. Several explanations have been offered for these findings.

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