This 28-day study (3) compared alprazolam and placebo in 462 clinically anxious patients whose depressed mood indicated at least moderate severity in the Hamilton Anxiety Rating Scale (HARS). The patients ranged in age from 18 to 70 years. Patients with obvious sociopathy or psychosis, primary affective disorder, or alcoholism, and those requiring medication other than the study drugs were excluded, as were patients who were known to be sensitive to ben­zodiazepines or who had serious liver, kidney, cardiovascular, or pulmonary disease. After a 4- to 7-day washout and screening period, the patients were randomly assigned to alprazolam (242) or placebo (220) regimens within a dosage range of 2 to 12 capsules per day (0.25-mg alprazolam capsules). The patients’ anxiety symptoms were assessed at the beginning of the treatment period and after 1, 2, and 4 weeks of medication on the HARS, a 35-item Self-Rating Symptom Scale (SRSS), a Target Symptoms Record, and the Patient’s and Physician’s Global Impressions scales. Side effects, or treatment-emergent symptoms, were recorded on a symptom and side effects checklist initially and at weeks 1, 2, and 4; symp­toms that appeared or worsened during treatment were considered side effects. Alprazolam was more effective than placebo in relieving anxiety associated with depressed mood on every efficacy measurement of each assessment period. By the fourth week, the difference between the two treatment groups was sig­nificant (p < 0.012) on almost every item of both the HARS and the SRSS (2,3). According to the Patient’s Global Impressions of how much change had oc­curred and the Physician’s Global Impressions of therapeutic effect, more than 75% of the patients given alprazolam responded favorably, whereas less than one-third of patients given placebo responded to treatment. The treatment-emergent symptom reported most often was drowsiness, which did not differ significantly in frequency between the groups. No other treatment-emergent symptom was reported by a significant number of patients in either group. Side effects caused four patients on placebo but no patients on alprazolam to drop out of the study.

Institute of Psychiatry, University of Milan, School of Medicine, 20122 Milan, Italy
In 1894 Freud (21) proposed the separation of anxiety neurosis from neuras­thenia. Since then, there has been intensive theoretical and extensive experimental work on the relationship between anxiety and depression. Nonetheless, we still cannot firmly conclude whether anxiety and depressive disorders are distinct entities. Our clinical experience, however, has unquestionably demonstrated that symptoms of anxiety very frequently color the picture of depressive disorders, so much that the label "anxious depression" is widely used in spite of the fact that it is not a category recognized by most of the latest diagnostic systems. The presence of symptoms of both anxiety and depression in clinically de­pressed patients definitely does not appear to be confined exclusively to depressive neurosis or to other minor types of depression. Anxiety is also present in patients that are readily diagnosed as having either some of the traditionally defined disorders, such as manic-depressive psychosis or endogenous depression, or the operationally defined major affective disorders. A few examples will suffice to confirm the presence of anxiety in major depres­sion. Factor analysis (12) has shown that, at the very least, the anxiety and depressive factors loaded equally in over 65% of the cases of a sample of patients with endogenous depression. Similarly, a recent study (2) demonstrated that as many as 25% of the patients with major depression and 10% of those with brief recurrent depressions had an overlapping anxiety disorder as well. On the other hand, an ever-increasing body of data from genetics, biochemistry, neuroendocrinology, neuromorphology, and clinical psychopharmacology (8,25,31,43,46,47,53,55) indicates that major depression is not a homogeneous disorder, but subsumes a number of biologically and, perhaps, etiopathogenetic distinct subforms. In order to understand the presence of anxious symptomatology in major depressives it seems particularly important to look at this problem in the light of the inherent biological heterogeneity of major depression. Although prelim­inary, recent reports (6,54) of different familial incidence of major depression among the first-degree relatives of depressive patients with and without associated panic attacks or agoraphobia suggest that specific anxious symptoms are pref­erentially clustered in distinct subtypes of major depression. In order to explore this hypothesis, we undertook a series of exploratory anal­yses specifically designed to test whether some biochemical, pharmacological, and clinical variables, usually singled out as putative markers of the heterogeneity of major affective disorders, could be useful in screening major depressive patients who would consistently present anxiety symptoms. This chapter summarizes the findings from these preliminary studies, soma of which are still underway.

Paula J. Clayton Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota 55455
Clinical investigators have long been able to distinguish between the two psy­chiatric syndromes originally known as manic depressive insanity and anxiety neurosis. Kraepelin (9) wrote eloquently on the mood state and symptoms seen in melancholia: The fundamental mood in the state of depression is most frequently a somber and gloomy hopelessness. . . . More rarely, anxiety is the principal feature. Sometimes it is more inward anxiety and trembling, a painful tension which can rise to mute and helpless despair. Sometimes it is an uneasy restlessness. In other cases, it is a peevish, insufferable, dissatisfied and grumbling mood. Everything torments, annoys, irritates, fills the patient with bitterness; the sunshine, people enjoying themselves, music, everything done and left undone in the surroundings. Although Kraepelin felt that anxiety and agitation were frequently the transition between mania and depression, he also recognized anxiety as part of the depressive syndrome. On the other hand, Freud (7) described the nervous symptoms of the anxiety state that led him to use the term anxiety neurosis. In the 1950s clinical researchers extended our knowledge of these two syn­dromes by publishing studies that required specific criteria for inclusion and exclusion, systematic inquiry into symptoms, appropriate controls, even follow-up, and family history data. Wheeler et al. (16) published a 20-year follow-up of 173 patients with neurocirculatory asthenia (anxiety neurosis, effort syndrome, neurasthenia) and delineated the more specific syndrome resembling anxiety neurosis. They did not acknowledge psychological depressive symptoms as part of the picture, but did report overlapping vegetative depressive symptoms such 3s fatigue and insomnia. In the same department, in their classic paper on clinical observations in manic depressive disease, Cassidy et al. (5) designated patients tor the study who had mood changes that included any of the following terms: blue, worried, discouraged, depressed, anxious, low, scared, fearful, angry, afraid, Bloomy, hopeless, despondent, do not care, empty, disgusted, as well as the veg­etative and psychological symptoms with which we are now very familiar. They reported that 33% of these patients had classic anxiety attacks, and 62% described some sort of "spell" that included anxiety attacks, dizzy spells, confused spells, and undetermined spells. Marks and Lader (10) summarized the dilemma by writing, like other emotions anxiety can occur in a wide range of clinical states. It is a common feature of affective disorder, the agoraphobic syndrome, and obsessive-compulsive disorder. While it can be a symptom of schizophrenia, conversion syndrome, organic confusional state, or epilepsy, where anxiety dominates the clinical picture, in the absence of other gross disorders, the term anxiety state should be used. It denotes a cluster of symptoms based on fear, the source of which is not recognized by the patient. With the advent of structured interviews, research diagnostic criteria, and DSM-III (1), the common sense of clinical psychiatry sometimes seems to have been lost. By defining agoraphobia, panic disorder, and generalized anxiety dis­order as separate disorders (with only the last two being excluded if attributed to major depressive disorder), the field runs the risk of losing the two specific clinical syndromes of anxiety neurosis and depressive illness. Despite an excellent review by Breier et al. (4) on the diagnostic validity of the anxiety disorders that concluded that there was strong support for the diagnostic validity of panic disorder, but few data to support a separate diagnostic classification of generalized anxiety disorder, the syndrome continues to be represented in DSM-III-R (17). Although DSM-III-R has rescued part of the anxiety syndrome by recognizing that panic attacks and agoraphobia are related, the authors of it have amplified the overlap of generalized anxiety disorder with major depressive disorder by requiring for the former that the A symptom be 6 months of "excessive worry" (a symptom that occurs in 75% of patients with pure depressive disorder) and by not making the presence of major depressive disorder an exclusion criterion. Tyrer (15) recently proposed grouping together the three anxiety disorders, which would return the syndrome to the 1950 concept of anxiety neurosis. If we re­member the criteria of Marks and Lader (10) for an anxiety disorder, that anxiety must dominate the clinical picture in the absence of other gross disorders, then the situation becomes clear. In the presence of another gross disorder, depression, an anxious depression appears as a potentially interesting subtype. Given that psychiatry has difficulty distinguishing between two major disorders, it is not surprising that it also has difficulty in subtyping depression. Many authors have used the terms anxious depression, agitated depression, and involutional melancholia interchangeably. The majority of data on involutional melancholia has not supported the continuation of the subtype, and thus it was deleted from DSM-III and ICD-9. How and if anxious depression, however, overlaps with agitated depression has not been well considered. In first reporting on his rating scale for depression in 1960, Hamilton (8) found that the primary factor resem­bled a retarded depression, but a second factor emerged that resembled agitated depression with loadings on agitation, insomnia, anxiety, hypochondriasis, gas­trointestinal symptoms, and weight loss. A more recent multivariate analysis by Overall and Rhoades (13) of the Hamilton Depression Rating Scale on depressed patients entered into clinical psychopharmacology drag trials indicated that in 420 profiles, five preliminary clusters emerged: anxious, suicidal, somatizing, vegetative, and paranoid. The anxious type was identified by elevated levels of depressed mood, psychic anxiety, and initial insomnia. Other potentially im­portant symptoms were agitation and obsessive-compulsive symptoms. The au­thors postulated that, because of the symptoms, the anxious subtype might be milder than the other subtypes. The authors made no attempt to correlate the subtypes with age, sex, race, outcome, or family history. Thus, whether the sub­type is clinically meaningful, many studies have shown an association between anxious and agitated symptoms and included it as a subtype of depressive dis­orders. More recently, Fawcett and Kravitz (6) have looked at anxiety symptoms as they occur in depressive illness. Using 200 in- and outpatients diagnosed as major depressive disorder using the SADS and RDC criteria, they found that 72% of these patients reported moderate worry, 62% reported psychic anxiety, 42% reported somatic anxiety (autonomic and muscular symptomatology), 29% panic attacks, 19% reported phobic symptoms, and 1.2% obsessive-compulsive symptoms. These anxiety ratings correlated positively with also being of the endogenous subtype on the SADS. Further unpublished data on an expanded sample confirms these findings. The majority of depressed patients when inter­viewed systematically reported the whole spectrum of anxiety symptoms, with worry and psychic anxiety being the most common. Other anxiety symptoms such as discouragement, insomnia, lack of energy, somatic concern, deperson­alization, subjective anger, distrustfulness, as well as decreased concentration and classic diurnal variation, correlate significantly with this anxious depression. How this subtype correlates with other variables such as age, sex, outcome, treat­ment, and family history is not yet understood. In the Fawcett and Kravitz paper (6) the authors noted that by finding that a substantial proportion of depressed patients also report
ed anxiety symptoms, clinicians were forced to consider this in planning management and predicting treatment response. They pointed out that in the future, it may be used as a guide in determining which antidepressant might be most appropriate for which patient. They also theorized that if anxiety symptoms were not controlled early in the treatment of depression, they may produce noncompliance and premature termination. More recent work with the use of anxiolytics in depressed states may also need to be reviewed in light of these findings. In contrast to the suggestion of Overall and Rhoades, based on patients’ initial symptoms only, that anxious depression may be milder, more recent studies concluded the opposite —anxious depression or mixed anxiety and depression have the worst prognosis. Stavrakaki and Vargo (14) found that when anxiety and depression coexist, function is most impaired. They reported increased chronicity of illness, reduced response to conventional therapies, and a poorer Prognosis. Two recent epidemiologic studies confirmed this. Angst and Dobler-Mikola (2), in a field sample of young men and women, reported that most of the anxiety syndromes (anxiety states, simple phobia, social phobia, agoraphobia, panic attacks) coexisted. They also found in comparing various subgroups of depressives and anxiety disordered subjects that those with diagnoses of depression and anxiety had the highest frequencies of serious depressive symptoms and, as expected, more symptoms on the SCL-90 scales of depression, anxiety, and pho­bias. Murphy et al. (12), in a follow-up study of the "cases" of depression and anxiety in the Sterling County study, found a poorer outcome in those who were depressed compared to those who were anxious. The worst outcome was in those with depression and anxiety, although they resembled closely the depression-only study group. An interesting result of this study is that even in a community sample like this, the number who are depressed and anxious (N = 24) was three times greater than those with pure depression (N = 8). A further morbidity study of this population (11) confirms a poorer outcome for the total group of de­pressives. In summary, there seems to be a sizable group of classic depressed patients who report along with depressed mood, symptoms of worry, anxiousness, tense­ness, fearfulness, panic attacks, phobic, and obsessive-compulsive symptoms. These patients appear to have many other symptoms that we have previously associated with endogenicity (especially diurnal variation). Despite their high scores on anxiety, in current studies they receive no specific treatment; the symp­toms go unrecognized, not verbalized, or minimized. Although early studies, probably combining a number of outpatients with inpatients, indicated that the anxious depressives were the most mild and resembled "the old neurotic depres­sion," more recent studies have all coalesced to conclude that the overlap of anxiety and depression predicts the most serious outcome, including poorer treatment response, more chronicity, and higher mortality. This subtype of depression demands further study. (more…)

Basically, the relationship of early traumata to adult life depression may be studied by either prospective or retrospective studies. In the first case, the in­dependent variable is the occurrence of an early trauma, whereas the dependent variable is whether a subsequent illness occurred. The opposite position applies to retrospective studies, i.e., that the presence of an illness being the independent variable, the researcher looks for the presence of early traumata. Both methods are difficult to carry out in practice because of serious meth­odological limitations. Prospective studies are almost impossible in man, because of the length of the observation period, whereas retrospective studies are seriously biased by the fact that the events have to be recalled at a distance of several decades. In this case the researcher is caught between the lack of sensitivity of the methods that consider only those events that may be reliably recalled (e.g., death of a parent), and the lack of reliability of the methods that take into account finer, but less objective events, e.g., the quality of the upbringing patterns. In man, the prospective procedure has been followed in Sweden by studying
the prevalence of psychiatric disorder among adoptees. In this case, while a slight overrepresentation of psychiatric illnesses has been found during the adult life of adoptees (compared to nonadopted people), it was not possible to establish a precise relationship with affective disorder, except, perhaps, a dubious association with depressive neurosis (4,49). Retrospective studies may be made by the administration of specially devised questionnaires [the last one is the EMBU (39)]; the studies carried out with this method are fairly consistent in showing that depressives perceive their childhood more negatively than healthy people, although the same findings were not valid for the bipolars (36). Self-assessed inventories, however, aim to investigate the subjective perception of the events, rather than the actual occurrence of the events. The majority of studies has therefore used the method of considering only the events that can be objectively and reliably re-evoked. Table 1 summarizes the controlled studies in this area. It may be noted that after some initial discrepancies among the earlier studies, the most recent show a general tendency to find an excess of early traumatic events in depressives. In our own study (16), two distinct groups (100 and 118 cases, respectively) of patients with a DSM-III diagnosis of Major Depressive Episode were compared with two control groups, of 100 cases each, made up of mixed psychiatric patients and healthy subjects, respectively. While there was a general excess of early traumata in the affective patients, the differences were small, at a much lower degree hypothesized by the psychological model of the illness. Furthermore, it may be objected that depressives run a greater risk of experiencing childhood traumatic events because of a greater psychiatric morbidity in the family circle. In our sample, for instance, we found that some cases of separation from parents were owing to admission of either parent to a psychiatric hospital; some cases of divorce were secondary to alcoholism or sociopathy, and so on. When we tried to single out such events and repeated the comparison, the differences became much smaller, although retaining some statistical significance. Overall, therefore, it would seem that depressives suffered more traumatic events during their childhood, compared to nondepressives, but the difference is too small to support conclusively any model of the illness based on these grounds. These kinds of studies, however, are subject to a basic criticism: The psychological models of depression are concerned with the quality of events, rather than with their crude objectivity. The lack, or the smallness, of the dif­ferences would therefore result from the fact that the method is not able to reveal the actual personal psychological impact of the events, rather than from the non-validity of the theory being tested. One response could be that when a real, consistent difference does exist, it emerges clearly even with such clumsy meth­odology. When we used the same method to evaluate the life events of patients with agoraphobia (18), a clear and significant excess of early traumata was found over the healthy controls, despite a lower number of cases. In conclusion, therefore, our impression is that, at the moment, there is no conclusive evidence for a strong implication of early life events in the pathogenesis of depression, although an association between events and depression does exist. Three different hypotheses may be considered: (a) The initial hypothesis, as derived by the psychoanalytic model of depression, is only partially valid; an early trauma, although an important factor, would not be as crucial to the de­velopment of affective illness as the theory suggests, (b) The methods used to quantify early events are too clumsy to capture the emotional impact of these events on the child, (c) Other factors, apart from those considered in the psy­chological model, play an important role in the etiology of this disorder. (more…)

1. Freud, S. (1915/1950): Mourning and Melancholia. Collected Papers, Vol I. London, Hogarth Press and the Institute of Psychoanalysis. 2. Klein, M. (1960): Our Adult World and Its Roots in Infancy. Tavistock Publications, London. 3. Rado, S. (1951): Psychodynamics of depression from the etiological point of view. Psychosom. Med., 13. (more…)

It has been suggested that the facilitation of the GABAergic transmission in­duced by benzodiazepines plays an important role in the antistress and antianxiety effects of these drugs (4,7,35). On the basis of this hypothesis, we evaluated whether anxiolytic benzodiazepine receptor ligands were able to antagonize the decrease in the density of low affinity GABA receptors induced by electrical foot-shock stress in rats. As shown in Table 3, the in vitro addition of diazepam (5 mM to cortical membrane preparations from foot-shocked rats increased the density of low affinity GABA receptors to the level found in nonstressed animals. This finding indicates that in the rat cerebral cortex, benzodiazepine receptors are functionally linked to the low affinity GABA receptors and may play a critical role in the regulation of emotional states. Recently, a novel series of b-carboline derivatives with pharmacological prop­erties opposite to those of anxiogenic b-carbolines have been synthetized. Among
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