The University Department of Psychiatry, The Royal Liverpool Hospital, Liverpool, L69 3BX, England

The prevalence of depression in the original random sample of 1,070 com­munity subjects was 11.3% overall (8.3% for depressive neurosis, 3.0% for de­pressive psychosis). Of the total sample, 2.7% reached case levels (diagnostic confidence level 3 and above) on both depression and anxiety clusters, or 24.0% of the depressive cases as a whole, or 70.7% of the anxious cases as a whole. Table 1 shows the percentage prevalence for subjects having coexistent levels of depression and anxiety after other diagnoses, e.g., organic states, schizophrenia,
hypochondriasis, obsessional and phobic states, had been excluded. Of the whole sample, 3.8% reached case level for anxiety and 32.2% reached subcase level; 11.7% of the total sample reached a subcase level of depression and of the 8.3% with depressive neurosis, 4.9% and 1.8% reached subcase and case levels of anx­iety, whereas, of the 3.0% with depressive psychosis, 1.9% and 0.9%, respectively, reached subcase and case levels of anxiety. Thus, although the association of depressive levels with anxiety levels was common, 83.5% of cases of depression were associated with some levels of anxiety; those with coexistent case levels of both depression and anxiety seem to represent only a small proportion of elderly subjects. The outcome of the subjects in the study at this stage in the analysis is expressed crudely as dead, well (no confidence level on any diagnostic cluster), and psy-chiatrically ill (reached case level 3 and above on a diagnostic cluster). The first 80 subjects followed up after 3 years are reported. Ten of these 80 subjects with depressive case levels refused interview. The death rate of the subjects as a whole over the three years was 18%, or 6% per year, but was higher for the depressive sample at 27.1% or 9% per year. In order to compare outcome on these three indices the sample was split in a number of ways. The sample was separated into those depressive cases that had no anxiety confidence levels (14) and those depressive cases that had some anxiety levels (56) (Table 2). Although there is a tendency for a higher proportion of those subjects with depressive case levels and anxiety levels to be well at the end of three years, the differences do not reach statistical significance. The subjects were divided into those depressive cases with no AGECAT anxiety levels taken together with those scoring level 1 (19), against those scoring AGECAT anxiety levels 2 to 5 (51). Those depressive Read the rest of this entry »

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.
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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 Read the rest of this entry »

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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Independent information from epidemiological, clinical, biological, and phar­macological research impels formulation of the hypothesis that suicidal tendency represents a behavioral characteristic typically concentrated in specific subgroups of major depressives. Epidemiologically, the tendency for suicide attempters to repeat self-destructive acts is a rule rather than an exception. Clinically, suicide proneness has been shown to be associated with delusional depression (40). When major depressive suicide attempters were biologically compared to nonattempters, it was found that the patients in the former group had: a different genetic makeup (48); critically lowered CSF concentrations of 5-HIAA (7,52) and possibly HVA (34); increased chances for higher 17-OH-corticosteroid urinary concentration (10); lowered MAO platelet activity (9); higher melatonin plasma levels (4); ce­rebral ventricular enlargement (28,35); and augmenting average evoked responses (2). Further, in post-mortem studies of specific brain areas suicide attempters present either subnormal 5-HT concentrations (7) or supranormal densities of 5-HT 2 receptors (38,50). Pharmacologically, a history of suicidal behavior seems to have predictive value for a poor response to lithium therapy (45,46). Assuming suicide proneness as a marker of a distinct subgroup of major af­fective disorders, we analyzed the distribution of autoaggressive antecedents among definitely nonanxious major depressives. Previous suicidal behavior was indeed specific to the anxious depressives. Fourteen of the 15 patients composing our group of suicide attempters also were definitely anxious depressives whereas the relationship between anxiety-no anx­iety in the group of 60 nonattempters was exactly 1 (x 2 = 7.59, p = 0.006; odds ratio = 14). Since the information on suicidal behavior was collected after the cases were classified as anxious or nonanxious, the observed association cannot now help us to deal with the issue of whether suicidal behavior represents a consequence of collapsing anxious defenses. What we can say is that anxiety and suicidal behavior may have generally common or similar pathogenetic determinants and a partially interchangeable functional significance, for example, the patient’s attempt to alleviate his suffering from depression.

St. Francis Day Hospital, Dublin 5, Ireland Read the rest of this entry »

Studies undertaken during the late sixties (19,32) report a reduction in urinary MHPG excretion in depressed patients as compared to normal controls. This peripheral index undoubtedly is one of the most frequently used tools in research on the catecholaminergic correlates of affective disorders (31,43,44,53). Even if there is still some uncertainty about this measure, it seems sufficiently reliable for us to use it as a basis for subdividing major affective disorders into two fundamental subtypes, the relatively low and high groups. We ourselves found a bimodal MHPG excretion distribution among 153 drug-free patients with major affective disorders (Conte et al., unpublished report). Furthermore, and more importantly, relatively low and high excretors differ in age at onset (5,13,42,53), the number of platelet alpha-2-adrenoceptors (43), urinary Cortisol levels (41), cerebral ventricular size (53), clinical responsiveness to both antidepressant drugs (31,44,47,53) and long-term lithium treatment (45,46), and, possibly, a proclivity to develop mania (31). As for the MHPG relationship with symptoms, the emerging picture is that none of the latter in itself is sufficiently able to influence MHPG excretion so that the division of the patients into low and high excretors is appreciably affected, despite the fact that a slight effect on MHPG cannot always be excluded (31,42,44). This general conclusion also appears to be applicable to anxiety. As previously noted, studies focused on anxiety symptoms may inevitably unify mere situational phenomena with well-established traits. At the same time, it is extremely difficult to take into account the possibility that these traits sometimes can be effectively masked by positive chance circumstances and thus elude clinical detection. Con­sequently, studies of the relationship between MHPG excretion and anxiety in depression have not addressed the issue of whether the biological phenotypes of low and high excretors indicate a markedly different susceptibility to anxiety. With the latter as the investigational framework, we compared the MHPG excretion of 29 definitely anxious patients (14 males, 15 females) with major affective disorders with that of 16 definitely nonanxious ones (4 males, 12 fe­males). Since our general sample median MHPG value for males tended to shift to the right of that for the females, we used sex as a supplementary variable in the two-way ANOVA analysis of the present data. This indicates that being both male and definitely anxious positively, but independently, affects MHPG excre­tion (sex effect: F (1,41 ) = 1535, p = 0.001; anxiety effect: F (1,4 i) = 6AS,p = 0.016; interaction: F (l,41) = 0.03, p = NS). Independent nonparametric analyses after division of the patients into defi­nitely low and definitely high MHPG excretor groups (cut-off points: the median values of 1,650 Mg/24 hr for males and 1,119 /ug/24 hr for females) clearly indicate that the association between high MHPG excretion and anxiety is a strong one. The finding that 88.5% of the 26 high excretors (23 patients) were definitely anxious and that 32% of the 19 low excretors (6 patients) were definitely non-anxious means that the relative risk of anxiety is fully 16.6 times greater in the former than in the latter biochemically defined group. Thus, anxiety traits unrelated to the chance circumstances surrounding any particular episode are not randomly distributed among patients with major de- pressive disorders. On the contrary, they are strongly associated with readily distinguishable biochemical patterns.