Product moment correlations between these scales derived in this study are shown in Table 4. The correlations between the scales measuring anxiety and depression are still much too high. They are almost of a magnitude of those supposedly measuring depression alone. The BDI/ZDS correlations with the Hamilton are not as good as one would like. In Table 5 one can see that the correlations of the SCL-90-R in depression and anxiety are very high on all the scales. The dimensions of anxiety and depression in the SCL-90-R are not there-fore reflecting adequately different syndromes. It was found for these established scales that there were striking similarities in the mean scores, ranges, profile of item scores, and factorial structures between
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Department of Experimental Biology, Chair of Pharmacology, University of Cagliari, 09100 Cagliari, Italy
Benzodiazepines, the drugs most widely used in the treatment of anxiety, produce their pharmacological effects by regulating the interaction of GABA with its recognition site at the level of the GABA/benzodiazepine receptor com­plex (17,18). In fact, it has been shown that benzodiazepines favor, through an allosteric mechanism, the interaction between endogenously released GABA and its recognition site. Thus the anxiolytic effect of benzodiazepines may be con­sidered the consequence of the activation of the GABA receptor induced by these drugs. Accordingly, in different animal models of anxiety, the anticonflict effect of benzodiazepines is antagonized by picrotoxin and bicuculline (4,35), drugs that reduce the responsiveness of GABA receptors and have an anxiogenic effect on their own (12,27), whereas it is mimicked and potentiated by muscimol, a specific GABA receptor agonist (7). Moreover, it has been found that /S-carboline derivatives, benzodiazepine receptor ligands (5) that modulate the GABAergic function in the opposite direction to the benzodiazepines (2,6,8,11,21,26,29) have an anxiogenic effect in several animal species, man included (14-16,23, 25,27,30). Although the above studies have clearly demonstrated that the GABA/ben­zodiazepine receptor complex participates in the anxiolytic effect of benzodi­azepines, the molecular events involved in the physiopathology of stress and anxiety have still to be clarified. With the aim of clarifying this problem we have recently found that stress selectively reduces the density of low affinity GABA receptors in the cerebral cortex of the rat (1,3,9,13). This finding is consistent with the hypothesis that some emotional states related to stress and anxiety may result from a diminished GABAergic transmission at the level of the GABA/benzodiazepine receptor complex. The finding that brain GABA receptors may be modified by the emotional state of the animal before sacrifice was obtained a few years ago in our laboratory when we found that the cerebral cortex of rats habituated to the manipulations that precede sacrifice by guillotine has a higher density of low affinity GABA receptors than that of naive, nonhabituated animals (Table 1). On the basis of this result we speculated that the handling manipulation con­stitutes, for a naive animal, a stressful stimulus sufficient to induce a decrease in the density of GABA receptors. To confirm this hypothesis we studied the effect of electrical foot-shock on the binding of 3 H-GABA in the cerebral cortex of naive and handling-habituated rats. Foot-shock, delivered just before sacrifice to these two groups of rats, decreased the density of 3 H-GABA binding sites in cortical membrane preparations from handling-habituated rats, but failed to further decrease 3 H-GABA binding in those of naive ones (Table 1). From these results we concluded that handling-habituated rats represent a relatively nonstressed condition, whereas the handling of naive animals just before sacrifice or the electrical foot-shock are stressful stimuli able to cause a decrease in GABA receptors. To further clarify the molecular mechanism that mediates the decrease of GABA receptors elicited by stress we studied whether the effect of stress was mimicked by anxiogenic /J-carboline derivatives, benzodiazepine receptor ligands that down-regulate the GABAergic function (2,6,8,11,21,26,29). As shown in Table 2, the in vitro addition of different /3-carboline derivatives to cortical membrane preparations from unstressed (handling-habituated) rats decreased the number of low affinity GABA receptors to approximately the same (more…)

1. Akiskal, H. S. (1983): Am. J. Psychiatry, 140:11-20. 2. Akiskal, H. S. (1983): In: Affective Disorders Reassessed, edited by F. Ayd, I. J. Taylor, and B. J. Taylor, pp. 125-137. Ayd Medical Communications, Baltimore. 3. Akiskal, H. S. (1983): Psychiatric Developments, 1:123-160. 4. Akiskal, H. S. (1984): J. Affective Disord, 6:287-295. 5. Akiskal, H. S., Lemmi, H., Yerevanian, В ., King, D., and Belluomini, J. (1982): Psychiatry Res., 7:101-110. 6. American Psychiatric Association. (1980): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. American Psychiatric Association, Washington, D.C. 7. Davidson, J. T. R., Miller, R. D., Turnbull, С D., and Sullivan, J. L. (1982): Arch. Gen. Psychiatry, 39:527-534. 8. Dube, S., Kumar, N., Ettedgui, E., Pohl, R., Jones, D., and Sitaram, N. (1985): Biol. Psychiatry, 20:408-418. 9. Feighner, J. P., Robins, E., Guze, S. G., Woodruff, R. A., Winokur, G., and Munoz, R. (1972): Arch. Gen. Psychiatry, 26:57-63. 10. Lloyd, G. E. R. editor (1983): Hippocratic Writings. Penguin Books, Hammondsworth, England. 11. Reynolds, С F„ Shaw, D. H., Newton, T. F., Coble, P. A., and Kupfer, D. J. (1983): Psychiatry Res., 9:81-89. 12. Roth, M., and Mountjoy, Q. (1982): In: Handbook of Affective Disorders, edited by E. S. Paykel, pp. 70-92. The Guilford Press, New York. 13. Sargent, W. (1961): Br. Med. J., 1:225-227. 14. Torgersen, S. (1983): Arch. Gen. Psychiatry, 40:1085-1089. 15. Uhde, T. W., Roy-Byrne, P., Gillin, J. C, Mendelson, W. G., Boulenger, J. P., Vittone, B. J., and Post, R. M. (1984): Psychiatry Res., 12:251-259. 16. VanValkenburg, C, Akiskal, H. S., Puzantian, V. R., and Rosenthal, T. L. (1984): J. Affective Disord., 6:67-82. 17. West, E. D., and Dally, P. J. (1959): Br. Med. J., 1:1491-1494.
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The activity of platelet MAO seems to be under strong genetic control. The hereditability has been estimated at 70% to 80%, according to twin studies (16). Within the individual, the activity of the enzyme seems to be stable over time, and thus it seems possible to regard this enzyme activity as a genetic marker (11). Low activity of platelet MAO has consistently been related to certain person­ality traits as sensation seeking, monotony avoidance, and extraversion (11,24). It was also demonstrated early on that subjects with low platelet MAO activity seemed to have an increased vulnerability with more psychopathology, more antisocial behavior, more experimentation with drugs, and more attempted sui­cides in their relatives (4). In patients with affective disorders, the results have been conflicting. In patients with unipolar or bipolar affective disorders, high, normal, and low platelet MAO activity has been reported (Table (10). In our own series, we tend to find
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This study uses the GMS-AGECAT package in order to assess the prevalence and outcome of anxious depression in elderly persons living in the community. The Geriatric Mental State (GMS) is a semistructured standardized clinical in­terview for assessing the mental state of elderly persons and for facilitating the making of a reliable psychiatric diagnosis. The full interview, which consists of 500 symptom items, was developed in response to the needs of our epidemio­logical studies in New York and London (2,5). Symptom profiles can be derived from this interview that show changes in levels over time, especially in response to treatment. The GMS items have been shown to be reliable between interviewers interviewing the same subject, and a clinical or intuitive diagnosis made by psychiatrists on the basis of the interview reaches good reliability. The full GMS interview was shortened using a series of linear discriminant function analyses to form the community version suitable for screening for mental illness, describing the mental state by symptom profiles and deriving a psychiatric diagnosis on community samples (GMSA) (6).In order to compare psychiatric diagnosis and prevalence levels of different studies, it was important not only to measure reliably the level of symptoms, but also to standardize the selection of a diagnosis and the decision whether the subject represented a case of illness. As a consequence the computerized diag­nostic system AGECAT, which runs to several thousand lines of FORTRAN, was developed (4). This system condenses the 157 symptom components of the mental state into 38 symptom subclusters that are in turn assembled under eight diagnostic clusters according to their importance for determining the certainty of diagnosis for that cluster. Each subject is allotted a level of confidence of disgnosis from 0 to 6 on each diagnostic cluster. Clusters are then compared level for level according to a hierarchy starting with organic disorder, including depression and ending with anxiety. At the end of this process the subject emerges with a main diagnosis, an alternative diagnosis if appropriate, the levels of con­fidence on all eight clusters, levels on 19 symptom components forming a profile of illness, depression and organic scores for quick case identification, and an organic/depression index, which our preliminary follow-up studies indicate has some success in predicting which subcases will become cases in later years (3) Cases of illness are not, of course, to be found in nature; they must therefore be defined for each study. However, psychiatrists generally seem to recognize a certain level or cluster of symptoms as forming a syndrome. When that point is reached we define it as a syndrome case. A subject may reach case level on several syndromes. The AGECAT method has the value that it allows us to examine subjects who reach case confidence levels on both the depression and anxiety clusters. The depression cluster is split into depressive psychosis (roughly equivalent to endogenous depression) and depressive neurosis (roughly equivalent to reactive depression). Syndrome case levels are at confidence level 3 and above. Levels 1 and 2 represent subcases. The AGECAT diagnostic system has been tested for validity against psychiatric diagnosis on a consecutive series of 150 hospital admissions and 396 community subjects, and in a replication sample on a additional 647 community subjects. Kappa values for the agreement between AGECAT and psychiatrists’ diagnosis reached 0.80 and above for organic disorders and 0.76 for depression. The data from our other interviews, the History and Aetiology Schedule for an informant, Social Status Schedule, and the Physical Status Schedule, are not reported here. The subjects described here formed part of a random community sample in Liverpool of 1,070, derived from general practitioners’ lists and interviewed in their own homes using the GMS-AGECAT package. The initial interviews were undertaken by four psychologists and one senior nurse trained in the method, whose ratings were shown to reach satisfactory reliability against those of the project psychiatrists (1). The follow-up study three years later was undertaken by psychiatrists interviewing the whole of the surviving sample using similar methods. Not all the data have been entered into the computer for the 3 year follow-up, and only the first 80 subjects with depression are reported here.

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.

A third study compared the efficacy and side effects of alprazolam, diazepam, and placebo in patients with anxiety (4). Of the 235 patients who participated in the 28-day study, 78 were given alprazolam, 85 were given diazepam, and 72 were given placebo. Two-thirds of the patients were diagnosed as having anxiety, one-third as having anxiety with depressive mood, and one patient as having obsessive-compulsive neuroses, according to the DSM-III classifications. Al­though patients had to be at least moderately anxious to be included in the study, the majority were diagnosed as being markedly, severely, or extremely anxious. At the end of the study, 80.3% of the alprazolam-treated patients and 60% of the diazepam-treated patients showed a moderate or marked improvement ac­cording to the Physician’s Global Impressions, whereas 62.2% of the patients who had received placebo showed no improvement or their condition worsened. The results of the other four evaluation scales, including the HARS, substantiated the effectiveness of alprazolam at an average daily dose of 1.5 mg and diazepam at an average daily dose of 18.6 mg. Side effects experienced by patients taking alprazolam were fewer and less
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