Since the two anxious subgroups did not significantly diffe r from each other with respect to any of the variables under baseline conditions, their MSLT, SSS, and HARS data have been pooled, and this body of data will be referred to as "baseline" for further comparisons.
Clinical Anxiety (more…)

1. Agricola, A., Mazzarino, M„ Agricola, R., and Urani, R. (1979): Clin. Ther., 2:399-408. 2. Association of Sleep Disorders Centers. (1979): Diagnostic classification of sleep and arousal disorders. 1st ed. Sleep, 2:1-137. 3. Bareggi, S. R Nielsen, N. P., Leva, S., Pirola, R., Zecca, L., and Lorini, M. (1986): Int. J. Clin. Pharm. Res., 6:309-314. 4. Bareggi, S R., Pirola, R., Leva, S., Nielsen, N. P., and Zecca, L. (1986): Eur. J. Drug Metab. Pharmacokmet., 11:171-174. 5. Bliwise, D., Seidel, W., Karacan, I., Mitler, M., Roth, Т ., Zorick, F., and Dement W С (1983V Sleep, 6:156-163. 6. Carskadon, M. A., and Dement, W. С (1982): Sleep, 5:S67-S72. 7. Church, M. W., and Johnson, L. С (1979): Psychopharmacology 61 309-316 8. Cohn, J. B. (1981): J. Clin. Psychiatry, 42:347-351. 9. Dement, W. C, Seidel, W. F., and Carskadon, M. A. (1982): Sleep, 5:S28-S45. 10. Greenblatt, D. J., Divoll, M., and Abernethy, D. R. (1983): Arch. Gen. Psychiatry 40287-290 11. Hoddes, E., Zarcone, V., Smythe, H., Phillips, R. L., and Dement, W. С (1973): Psy’chophysiology 10:431-436. 12. Johnson, L. C, and Chernick, D. A. (1982): Br. J. Clin. Pharmacol., 76:101-113 13. Roth, Т ., Roehrs, Т ., and Zorick, F. (1982): Sleep, 5:S128-S134. 14. Seidel, W. F., Ball, S., Cohen, S., Patterson, N., Yost, D., and Dement, W. С (1984)- SleeD 7-230-238. v ‘ 15. Seidel, W. F., Cohen, S. A., Wilson, L., and Dement, W. С (1985): Psychopharmacologv 87-194-197. 16. Seidel, W. F., and Dement, W. С (1982): Sleep, 5:S182-S190.
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The subjects were 10 anxious ambulatory patients whose demographic char­acteristics are shown in Table 1. The patients were diagnosed according to DSM-III criteria and found to have had a generalized anxiety disorder of variable duration (2-6 months) for which they had been receiving various somatic treat­ments that were withdrawn for an adequate period before starting the new treat­ment. Patients were accurately screened for concurrent major medical and neu­rological illnesses. Severe and persistent insomnia was ruled out through specific inquiry. Anxiety and depression ratings were obtained by means of the Hamilton Anxiety and Depression Rating Scales (HARS and HDRS) that were administered by a trained rater. As controls for a baseline MSLT comparison, we selected five subjects with an Association of Sleep Disorders Centers diagnosis (2) of persistent psycho­physiological insomnia (PPI) who had been kept off drugs for at least 3 weeks before sleep EEG and MSLT recordings. After the baseline clinical examinations, the patients were randomly assigned to receive either CDDZ 2 mg at 8:30 a.m., or APZ 0.5 mg at 8:30 a.m. and at 3:30 P.M. Subjects and raters were not unaware of the medication. Baseline MSLT recordings, however, were performed under placebo conditions and took place at 10 a.m., 12 a.m., 2 p.m., 4 p.m., and 6 p.m., according to standard rules (6). At the same times, patients subjectively rated their vigilance levels on the Stanford Sleepiness Scale (SSS) (11), and a venous blood sample was drawn for later parent drugs plasma levels determination. Blood pressure and heart rate were also monitored manually. MSLT sessions took place for every patient at day 0 (baseline), at the first day of drug administration (acute condition), and after 30 days of therapy (chronic condition). HARS, HDRS, and a side-effects list were filled out by the same rater at baseline and at days 14 and 30 of treatment. A venous blood drawing was repeated on day 30 of treatment, at the first (10 a.m.) and last (6 p.m.) naps. Plasma levels of parent compounds were assayed by electron-capture gas-liquid chromatography, as already described (3,4). Several dose adjustments became necessary after the first week of treatment in order to alleviate excessive residual anxiety or excessive daytime sedation. Among CDDZ patients, 3 of 5 required a reduction to 1 mg of the daily dose because of excessive subjective daytime drowsiness, whereas 2 subjects in the APZ group required a daily dosage increase to 2 mg and to 3 mg, respectively, because of excessive residual anxiety. All patients, however, continued to assume their drags according to the original time schedule. Nonparametric statistics (Friedman 2-way ANOVA and Kraskall-Wallis Г -test) were used to compare treatments and correlate vari­ables (Spearman Ranked Correlation).

Though the design of the present study does not conform with classical rules for clinical psychopharmacological trials, i.e., double-blind, placebo-controlled, and fixed-dosage protocols with larger patient groups, some interesting remarks on anxiety, anxiolytics, and daytime sleepiness can nonetheless be made in the light of recent publications on the subject. Generalized anxiety is well known to produce a state of CNS arousal that does not favor sleep in spite of the fact that anxiety and sleepiness can, at times, coexist. Our patients were moderately anx­ious (total mean HARS score: 22) and complained of some sleep difficulty at night, although unable to compensate for whatever sleep loss might have occurred during the daytime. As compared with patients suffering from persistent psychophysiological in­somnia who are also anxious but experience their daytime peak of anxiety just before going to bed, generalized anxiety disorder patients have a persistently elevated level of arousal throughout the daytime (Table 1). Seidel et al. (14) have found a minor percentage of such subjects (14%) in a large group of chronic insomniacs. Whether this tendency to high CNS arousal interferes with nighttime sleep onset or sleep maintenance cannot be determined by our limited obser­vations, but the timing of anxiety in the 24-hr sleep/wake cycle is now being considered as one relevant factor in managing appropriate anxiolytic therapy. The fact that subjective nighttime sleep quality was significantly improved after 2 weeks of treatment and remained stable after 1 month only through daytime sedation suggests that conditioned insomnia is not a major factor in generalized anxiety. Daytime anxiety was also effectively reduced by treatment, since no clinically significant differences were noted between a single daily administration of a long half-life compound such as CDDZ or a twice-daily regime of an intermediate half-life compound such as APZ. Starting doses (2 mg CDDZ and 0.5 + 0.5 mg APZ), however, had to be tailored after the first week due to different respon­siveness of individual patients on the anxiety-sleepiness continuum. During the treatment period, accumulation of both compounds occurred to a significant extent as proved by the chronic plasma levels that were, on average, five to seven times higher than those after acute administration. This is consistent with previous multiple-dose pharmacokinetic findings of CDDZ and APZ (4). The lack of significant correlation between individual SSS scores and objective values across the five sleep latency tests of each condition was not unexpected. Others have also shown that the across-subjects reliability of actual sleepiness ratings is low (7) and might be even less in patients than in normals, since the former may tend to confuse the sleepiness-alertness polarity with the anxiety-sedation one. The fact that the drugs’ plasma levels also did not correlate with MSLT values taken at the same time points supports the notion that daytime sleepiness profile is under the influence of several determinants (13). It has been demonstrated, however, that the buildup of plasma levels of benzodiazepines with chronic use is associated with a progressive partial tolerance to some of their clinical effects. Seidel et al. (15) gave 0.5 mg of APZ at 10 A.M. and at 2 P.M., to 9 healthy younger subjects for 7 consecutive days and found that their mean daily sleep latencies were significantly reduced as compared to baseline on both the first and the seventh day of administration. At the latter point, however, some tol­erance to the hypnotic effect was already evident. We have been able to show that the same occurs after 1 month of treatment in a small group of target subjects. In fact, mean MSLT value after acute APZ was significantly lower than at baseline (9.2 vs. 18.7 min), but was less so after 1 month of treatment (14.4 min), in spite of a greater mean daily dosage and a significant plasmatic buildup. Moreover, our MSLT data indicate that a single dose of 2 mg of CDDZ is also able to increase the mean daytime sleep tendency of anxious middle-aged subjects and that this effect is maintained after 1 month in spite of a reduction of daily mean dosage. Seidel et al. (15) obtained quite similar results after short and intermediate diazepam administration. On the first experimental day, 10 mg of diazepam produced less objective sleepiness than 1 mg of APZ, but subjects did not develop any tolerance to the sedative effect after 1 week of drug ingestion. Besides confirming Seidel’s conclusion that APZ’s initial higher sedative effect decreases within a short time, our data do suggest that this tolerance might selectively spare the anxiolytic effect that, according to HARS scores, is well maintained after 1 month of treatment. Hence, treatment with APZ would be indicated more in patients for whom a more selective effect on pure anxiety is desirable, whereas treatment with CDDZ would better favor patients who like feeling sedated in the daytime (16). Although appealing, such conclusions are still speculative and warrant more controlled trials with larger patient groups. One point, however, seems particularly relevant: Taking daytime sleepiness into account can help improve the effec­tiveness and standing of an anxiolytic drug therapy.

*Department of Psychiatry, University of Milan Medical School, 20161 Milan, Italy; **Department of Pharmacology, University of Milan Medical School, 20129 Milan, Italy; + Ravizza Clinical Research Laboratories, 20053 Muggio, Italy
The administration of long- and intermediate-acting benzodiazepines for the symptomatic relief of anxiety and mixed anxious-depressive syndromes is gen­erally viewed as safe and effective. Among the most widely prescribed anxiolytics in this country are chlordesmethyldiazepam (CDDZ), a derivative of diazepam’s major active metabolite with a half-life of about 83 hr in young adults (4), and alprazolam (APZ), a triazolobenzodiazepine with a half-life ranging from 11 hr in young males to 19 hr in elderly ones (10). Both drugs show the full spectrum of clinical and side effects of the classical minor tranquilizers and have been consistently shown to be more effective than placebo in the short- and long-term treatment of anxiety (1,8). The efficacy of the two compounds, however, has never been tested by direct comparison in a psychiatric population. As interest for newer and more selective anxiolytics grows, clinicians have shifted their attention from effectiveness against so-called target symptoms to a more solid concern for the short- and long-term sequelae of benzodiazepine administration (12). One of the most debated consequences regarding benzodiazepine hypnotics is the increase in daytime sleepiness above baseline levels. This has been both subjectively reported by patients receiving intermediate- and long-acting com­pounds in clinical doses, and objectively demonstrated for at least several days after the initial dose (5). Nonetheless, many anxious and anxious-depressed subjects appear to adapt quickly to the hypnogenic effect of anxiolytics, especially if the dose is slowly increased and well titrated against the more unpleasant symptoms. The intro­duction of standardized EEG laboratory techniques for the objective assessment of sleepiness, such as the multiple sleep latency test (MSLT) (6), however, has seriously challenged the reliability and accuracy of self-rated vigilance estimates (7). Some individuals seem to grossly over- or underestimate their capacity to maintain steady vigilance levels throughout the day. The inaccuracy seems par­ticularly evident in neurotic and anxious people who claim to be hyperalert even when taking sedative anxiolytics. In fact, subgroups of chronic insomniacs have been shown to have MSLT profiles similar to those of age-matched con­trols (14). Acute administration of hypnotic benzodiazepines produces daytime carryover effects that are dependent on the dose taken at night and on the pharmacokinetic characteristics of the compounds. Thus, the MSLT has been employed partic­ularly for the quantification of daytime residual effects on vigilance (9). It has been shown, for example, that short-acting hypnotics tend to produce less daytime somnolence than long-acting drugs (5). In fact, the MSLT can also be profitably applied for assessing the daytime somnolence of anxious patients who receive benzodiazepines exclusively during the daytime for the control of anxiety. This approach may be even more informative and clinically useful than the study of carryover effects since most anxious and anxious-depressed subjects need the anxiolytic effect, but not the excessive daytime sedation that causes a dramatic drop in their already reduced mental efficiency. In order to obtain a profile of daytime sleepiness in a target population, we have adopted the MSLT procedure in two groups of anxious middle-aged patients who were undergoing anxiolytic treatment with CDDZ and APZ. (more…)