While frequency distributions clearly differentiated the two groups on ecological and time allocation variables, the psychological reactions to similar situations, such as being alone or being at home, did not differentiate the groups significantly. A difference was found for the entire group, however, on thought congruence, a self-rating of thoughts, as focused on the activity that one is involved in. This measure differentiated both groups from other ES samples of mental disorders. For example, in contrast with schizophrenics, who are markedly more incon-gruent when they are alone (17), both anxiety groups were less congruent when they were away from home. The anxiety group then, interestingly, reports more disorganization when they are with people, whereas the schizophrenics report more unfocused thought when they are alone than when they are with company, In summary, for self-ratings of mental state, daily mean measures of affect, mo­tivation, and reactions to situations did not differentiate the medium and high groups.

The results of the various studies described now need to be discussed within a general framework. The first thing to highlight is that the associations were obtained from relatively small groups of highly selected patients in naturalistic settings. Consequently, supplementary controlled studies that also include less extreme cases will be necessary before generalizations become possible. Further, even in the case of the apparently more straightforward associations, it is evident that we are dealing with partial associations since there is a considerable degree of overlap between definitely anxious and definitely nonanxious major de-pressives. Because our work was specifically addressed to definite anxiety in major depression and not to the general occurrence of anxiety symptoms, extreme caution should guide comparisons with the findings from studies based on dif­ferent theoretical and experimental approaches. Despite these limitations, the accumulating biochemical, pharmacological, and clinical data in this area already appear to support the hypothesis that definite morbid anxious patterns phenotypically aggregate a particular subtype of de-pressives who are quite likely to have specific identifiable biological dysfunctions. Major depressives who also have morbid anxious symptoms were found to have a relatively high urinary MHPG excretion, poor response to lithium therapy, a late disease onset, and a history of delusions and suicidal behavior. As compared to this type of patient, the prototypical major depressive, relatively protected from anxiety, has a rather low MHPG excretion, no affective relapses during long-term lithium treatment, an early disease onset, and no history of suicide attempts or delusional symptoms. The clinical picture of anxious depressives is not really surprising. Its similarity to the classical Kraepelinian descriptions of involutional melancholia (29) im­mediately comes to mind. Further, it is worth noting that a similar symptom-grouping resulted from an earlier attempt (39) to differentiate discrete subgroups of depressed patients by factor analysis: one of these subgroups was characterized by high psychic and somatic anxiety scores, suicidal ideation, psychotic features, and a late disease onset. On the other hand, the fact that our definite morbid anxiety patients generally were the most impaired can also be viewed as a specific case of prior clinical evidence indicating that the more severe the depression, the more marked is the patient’s anxiety level (3,23,24,33). Consequently, our findings also can broadly represent further evidence supporting the hypothesis that anxiety and depression are two correlated dimensions (24). This is true, however, only if we limit our­selves to a purely descriptive clinical context. Our current knowledge of the biological correlates of the clinical aspects we found to be associated to anxiety symptoms, together with the findings on MHPG excretion and lithium therapy among anxious depressives, points to a substantial pathogenetic discontinuity among subgroups of depressed patients who appear to have a varying vulnerability to concomitant anxiety. Obviously, the research that has been undertaken to date is not sufficient for allowing a definitive answer to the question of whether the biological differences found really reflect distinct subtypes of major depression or if they are only indicative of a few main typologies. We shall have definite answers when we conduct studies that test, through stepwise, cluster, or multivariate techniques, whether we are observing first- or second-order associations or we are looking at additive or interactional effects. Yet, there is some indirect evidence that we can address at this juncture. A relatively high MHPG excretion was associated with a poor response to lithium therapy (45,46) and with a late disease onset (5,13,42,53). In turn, a poor lithium prognosis was associated with a late disease onset (45,46) and with delusional depression (46) and suicidal behavior (45,46). Further, delusional depression was associated with an increased probability of suicide attempts (40). Conse­quently, it seems reasonable to assume that many of the variables found to be associated with a definitely anxious major depression are indices (at different phenotypical levels) of a few main typologies. If further study definitively confirms this hypothesis, then the clinical category anxious depression might take on novel and stimulating meaning for the bio­logically oriented researcher as well, now often thinking of it as a label that the clinician sometimes abuses. ACKNOWLEDGMENTS This research was supported in part by the C.N.R. grant no. 86.01935.56. The authors thank Dr. June Shmelzer La Rosa for her precious assistance in revising the manuscript.

The results presented here show that a mild stress such as the handling ma­nipulation during the experimental procedure decreases the density of low affinity GABA receptors in the rat cerebral cortex. These data indicate that, in order to study the involvement of the GABAergic system in the physiological response to stress, we have to take into account the emotional state of the animals during the experiment. Accordingly, electrical foot-shock decreases the total number of low affinity GABA receptors in the cerebral cortex of handling-habituated rats, but is inef­fective in the cerebral cortex of naive animals. Most likely, the reason that explains the failure of foot-shock to affect GABA receptors in naive rats is that, for rats not habituated to handling, the manipulation before sacrifice constitutes a stressful stimulus responsible for the supramaximal decrease in low affinity GABA re­ceptors. It has been proposed that benzodiazepines exert their antianxiety effect by enhancing the GABAergic transmission in the brain (4,7,35). The finding that the in vitro addition of diazepam, ZK 93423, and ZK 91296 reverses the changes produced by foot-shock on GABA receptors inc’icates that benzodiazepine re­ceptors are involved in the action of stress on GABA receptors. This conclusion is also supported by the finding that those /3-carboline esters that bind with high affinity to the benzodiazepine receptors (5,6) and produce experimental anxiety in animals (14,15,23,25,27,30) and panic attacks in humans (16), share with stress (handling or foot-shock) the capability to down-regulate GABA receptors. Altogether these results indicate that cortical low affinity GABA receptors, coupled to benzodiazepine receptors, play a critical role in the regulation of emotional states. Compelling evidence indicates that in neuronal membranes the GABA receptor is part of a supramolecular complex that includes a chloride ionophore (24). Our experiments have shown that the function of the GABA receptor-coupled chloride channel is also modified by stress. Thus foot-shock reduces СГ efflux from cortical synaptoneurosome preparations of handling-habituated rats, but is ineffective in the same preparation from naive rats. These results, taken together with our previous findings, indicate that the GABAergic system plays a major role in anxiety and suggest that some emotional states related to stress and anxiety may result from a diminished GABAergic transmission at the level of the GABA/ benzodiazepine receptor/chloride ionophore complex.
(more…)

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.
(more…)