Between these subtly defined groups of high anxiety with medium depression and high anxiety with high depression as defined by Zung score, characteristic differences in daily activities and temporal aspects of anxiety and depression may be found using ES. This is particularly true for data at the behavioral level representing activities selected by the subjects in each group, and at the temporal level in terms of each group’s differential capacity to recover and rebound from high anxiety and depressed mood episodes. ES separated the groups on self-report scores of thought content, psychopa-thology, and time allocation of activities. Mean self-report scores of moment-to-moment mental states did not separate the groups nor did the situations in which they occurred. This finding suggests that anxious depression is relatively context independent. Further, behavioral changes seem a stronger indicator of changes in mental state than average scores of changes in the self-perception of state. Although much of the data presenting temporal relationships in this chapter are exploratory, we may tentatively conclude from the two findings, the slow decay of anxiety in the high depression group and the predictive trend of mood for anxiety, that depression in a day-to-day sense renders an individual more sensitive to anxiety. The basic pathological process in the phenomenology of anxious depression may therefore be depression. Although it may be a mea­surement artifact inherent in the Zung or Spielberger ratings, it is interesting to note in the context of this volume that in the sequential sample of 15 anxiety admissions reported here, none had a low depression score. The findings presented, when pursued further and in large samples, could lead us to a more comprehensive description of the phenomena of depression and anxiety in temporal and contextual terms. Such findings may not only be useful in solving current diagnostic controversies, but may also be useful in providing new avenues for treatment based on the frequency of the occurrence of the actual illness phenomenon, its context, and its temporal recovery properties. Such in-formation should be of significance to the clinician and the psychopharmacolo-gist alike.

REFERENCES (more…)

Recent biological theories of depression have focused on the possibility that changes in the function of noradrenergic (NE) and serotonergic (5HT) receptors might play a major role in the pathogenesis of affective disorders (23). The interest in studying biochemical changes after repeated antidepressant administration derived from the observation that the biological effects of antidepressants on monoaminergic systems occur within hours of administration, whereas their clinical effects on depressive symptoms have a latency time (2-3 weeks) (5,6). Studies on animals have revealed that chronic treatment with antidepressant drags lead to a down-regulation of beta-adrenoceptor complex and serotonergic receptors (1,11,17,18,31). This phenomenon might result from the prolonged contact of a set of receptors with their own neurotransmitter bringing to sub-sensitivity. These observations in laboratory animals have stimulated the investigation of receptor sensitivity in depressed patients. Platelets and lymphocytes have been used to assess peripheral alpha 2 and beta-adrenergic receptor function. The effects of antidepressants on neuroendocrine and behavioral variables have been used to evaluate central receptor activity (14,22). Decreased NE receptor sensitivity in depressed patients has been demonstrated with a number of pharmacological tests. For example, the amphetamine-induced increase of Cortisol and growth hormone secretion is blunted in depression (4). Diminution of the clonidine-induced rise in growth hormone, through the activation of postsynaptic alpha 2 receptors, has been demonstrated by several authors (3). Moreover, it has been shown that, during a prolonged treatment with anti­depressants, there is a good correlation between the improvement in the Hamilton score for depression and the lack of effect of clonidine in reducing blood pressure, meaning that alpha 2 receptors are desensitized (15). Studies with serotonergic agonists have also demonstrated subsensitivity of postsynaptic 5HT receptors in depression. In this context, it has been shown that the increase of prolactin, elicited by tryptophan and fenfluramine, is blunted in depressed patients com­pared with healthy controls (9,21). Besides antidepressants, it has been reported that alprazolam, a triazoloben-zodiazepine, is also able to affect beta-adrenoceptors in experimental studies. In fact, in animals pretreated with reserpine, when there is an up-regulation of beta receptors, alprazolam, unlike diazepam, did desensitize the hypersensitive beta-receptors (20). These findings underline that alprazolam might be considered as an atypical benzodiazepine and, besides its interaction with GABA receptor complex, that other mechanisms must be involved in its anxiolytic action. Recently we have focused our attention on imipramine binding sites, located presynaptically on serotonergic neurons, associated with the serotonin uptake system. This site is also present in platelets, and therefore there is now a great interest in studying these binding sites in psychiatric patients (12). It has been shown that these binding sites are reduced in the frontal cortex taken from suicides when compared to control subjects (24); thus, it seems of interest to study this binding site as a possible predictive biological marker. In the literature there are different reports on the modifications of these binding sites in platelets during different pathologies and different pharmacological treatments. 3 H-imip-ramine ( 3 H-IMI) binding has been reported to be decreased in the platelets of depressed patients, and this effect is specific, since in schizoaffective patients, there is no change (13). After medication with tricyclic compounds, the decrease in the number of binding sites seems to be reversed (25). In a preliminary study, we were able to show that in patients suffering from generalized anxiety and being treated with alprazolam, there is a tendency to an increase in platelet 3 H-imipramine binding sites in respect to time 0. Therefore, this benzodiazepine seems to behave in the same way as antidepressants. In an animal study, after chronic treatment with different antidepressants, there is a down-regulation of 3 H-IMI binding in rat brain (Fig. 1). These data
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Institute of Psychiatry, University of Milan, School of Medicine, 20122 Milan, Italy
Marked anxiety symptoms often accompany episodes of major depression (3,10,16,17,20), but the way in which such symptoms can be employed for sub-classifying affective disorders is still an unresolved issue. It has been suggested that anxiety symptoms may mark the more severe forms of depressive disorders (9). In fact, clinical ratings of anxiety and depression have been positively cor­related in patients with major affective disorders (4,8). Furthermore, a parallel increase in the number of DSM-III (1) defined symptoms of anxiety and depres­sion has been found in patients seen in primary care settings (9). If it is actually true that the more severe the major depression, the greater the probability of the presence of concomitant anxiety, depression with anxiety symptoms could be expected to be associated with the presence of other severity indices. One of the most promising of these recently has been shown to be cerebral ventricular dilation as assessed by Computed Tomography (CT). Ventricular enlargement has been found among the most severely and socially impaired depressives, those presenting characteristics such as delusional symp­toms (11,23,25,26), suicidal tendencies (11,15), frequent hospitalizations (18,19), persisting unemployment (18), and, at least in the elderly, high mortality rates (13). As part of a comprehensive effort to improve our knowledge of major depres­sion with anxious symptomatology (Sacchetti et al., this volume), we undertook a study to determine whether anxious and nonanxious major depressives have different brain morphological characteristics.

This paper will summarize data from studies conducted over some years into anxious depressions and their response to tricyclic antidepressants and MAO inhibitors. The studies have gradually led toward the conclusion that, although the MAO inhibitors may to a limited extent produce selectively better response in patients with a mixture of anxiety and depression, the tricyclic antidepressants are relatively broad spectrum drugs producing antidepressant effects over a wide range of depressive pictures. The concept of anxious depression is a somewhat diffuse one, rarely allotted a separate category in official diagnostic schemes or in textbooks. It overlaps with a number of alternative classifications. One of these is the endogenous neurotic distinction. Table 1 summarizes the findings from eight published studies that obtained factors reflecting the contrast between endogenous or psychotic depression and neurotic depression and that included ratings of anxiety. In three studies, anxiety loaded strongly toward the neurotic end of a factor and in two more it loaded weakly in this direction. In two studies it loaded weakly and in one study strongly in the psychotic direction. Two of these (30,32) differed from the remainder in having a unipolar endogenous factor without neurotic loadings rather than a bipolar factor, and one of the studies (31) reported separately a second self-pitying factor on which psychic and so­matic anxiety loaded highly. The endogenous first factors in both studies could alternatively be interpreted as general severity factors. Rotation from a bipolar factor structure with anxiety at the neurotic pole can produce a rather similar endogenous factor (23). Overall the findings do suggest some relationship be­tween presence of anxiety and a neurotic symptom pattern. However, the trend is not universal. In our own study, although anxiety loaded in the direction of
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of this book is to highlight some of the findings and considerations that could be significant for studying the severity of anxiety and depression. It is quite clear that we must distinguish between symptoms and syndromes in this area, and between rating measures and clinical diagnoses. It is equally apparent that there is a great deal of heterogeneity in these disorders depending on the type of patients dealt with: community samples, symptomatic volunteers from the community, general medical practice patients, or patients already in psy­chiatric settings. It is essential to relate the symptoms to the population in which they are measured, if we wish to know the real meaning of each symptom. Both anxiety and depression have their roots in the psychology of the individual, and they can be experienced also by nonpatients. However, their feelings are quite different from those found in psychiatric syndromes. We must use whatever instruments we have to determine the borderline between normality and pathology in this area. The coexistence of anxiety and depression is not necessarily always the same. In some cases, it is a depressive reaction that appears during a real anxiety disorder that clearly maintains psychopathological pre-eminence. In other cases, excessive anxiety as a symptom of recurrent major depression sets up an anxious depressive syndrome. External factors can be useful to define its nature in these patients. In other cases, we may have no landmarks, and anxious depressive syndrome seems to represent a single intermediate situation between the two extremes. The DSM-III attributes a priori a diagnostic-interpretative prevalence to the affective aspect, including depressive neurosis among affective disorders, and it does not exhaust the problem. This is why operative criteria should be used in order to organize the infor­mation reliably and establish linkages between symptoms that are probable if not definite, such as depersonalization and self-confidence, both of which have different significance in anxiety when compared to depressive disorders. It emerges that there are at least several distinct conditions characterized by a mixture of anxiety and depression. One has been called anxious-melancholia, which is equivalent to endogenous depression with anxiety. Moreover, recent psychopathological studies do also recognize the coexistence of major affective disorder and panic attacks. In these patients both diagnosis of axis I of the DSM-III are present. This condition is different from the coexistence of depression and anxiety as simple symptoms in the same patients. The amount of anticipatory anxiety may even overwhelm the depressive component and obscure the limits between the two conditions. Another type of disorder appears to be a classical anxiety disorder with the complication of secondary depression, with tendencies toward different types of chronicity of the depression, but all relatively insensitive to drug treatment. Finally, the most difficult condition to consider is an undifferentiated disorder with features of both anxiety and depression that are usually milder. These are the subcases that are probably overrepresented in community samples and in symptomatic volunteers. Despite the great degree of overlap in anxiety and depressive symptoms and syndromes when looked at cross-sectionally, there is considerable evidence that the two disorders are indeed distinct. For instance, retardation is quite charac­teristic in depressive disorders but not in anxiety disorders. The cognitive dif­ferences, uncertainty, and threat of loss are the major themes in an anxiety disorder, and hopelessness and desire for death in depression. Periodicity and seasonality are quite uncharacteristic of anxiety disorders, agoraphobia is quite uncharacteristic in uncomplicated depression, and suicide is more characteristic of mood disorders. Long-term recovery is also quite different. In anxiety disorder it is not terribly good, but in mood disorders long-term recovery is usually quite good. However, when patients seem to have combined conditions, the outcome might be some­what worse. There is much debate about genetic patterns in anxious depression, mainly because of the controversial findings of different groups. We still cannot reach a conclusion, and at least two alternative hypotheses have been proposed, a genetic and an environmental origin of anxious-depressive disorders. These dif­ferent hypotheses indicate a dichotomy between "state" and "trait" pathologies. In this sense, apart from the particular case of panic attacks, several types of neurotic illness, such as generalized anxiety or separation anxiety, might be viewed as due to environmental factors, whereas personality traits referable to "anxiety liability" could be mainly genetic. This last point introduces another issue of discussion on what is inherited. In the classical approach, the structure inherited is the liability to a particular disease. Alternatively, it has been proposed that what is inherited are the milder aspects of the various diseases and not their overt forms. To detect a view of the inner mechanisms that, based on genetic properties, control the manifestation of psychic major symptomatologies, it is important to see whether a subject pre­viously had a personality disorder. Unfortunately, this mode of thinking does not take into account the tremendous problem of heterogeneity in psychiatric genetics. In fact, it is well known that the so-called "phenotypic" similarities in psychiatry do not recognize common genetic backgrounds being related to various etiopathogenetic mechanisms. Neuropharmacological studies have shown that different neuronal systems are disturbed in both anxiety and depression in animals and humans. However, it emerges that the interactions among specific neurotransmitters, i.e., GABA, nor­epinephrine, and serotonin, seem to be of interest to explain the mechanisms of action of some pharmacological agents. Therefore, drugs that act on these neurons could manifest both antianxiety and antidepressant activity. Neuroendocrinological studies have not helped to differentiate between depression and anxiety disorders. Sleep data are preliminary, but there are studies suggesting that disorders can be distinguished on these bases. What do we need therefore to investigate? Special attention must be given to clinical measures. In addition to self-ratings, the psychiatrist must look at the effects on the patient. We need better measurements for psychomotor retardation and psychophysiologic responsivity. Moreover, cognitive features in depression anxiety and in combined syndromes must be considered. Early environment needs to be examined prospectively. Personality, as a subclinical expression of one or both disorders, needs to be studied more rigorously genetically. To make measurable what is not yet measurable is probably what is most needed in this particular area. Psychosocial functioning can be also looked at. Very elegant genetic models have been presented at this meeting, and they can be used to test spectrum models with larger sets of data. It might be useful to include personality functioning, personality disorders, and temperaments in these genetic models. Neuroendocrine and biological markers include urinary MHPG, platelet imipramine binding, 5-HT uptake, and sleep EEG. These variables should not be studied individually, as has been done so far, but as an entire complex of factors that underlie the clinical heterogeneity for both affective disorders and anxiety. This heterogeneity can never be overlooked, because it is the thoroughly established and productive aspect of our knowledge in this area. This is important because pharmacological response patterns should not be examined only as related to clinical features. It will be useful to include family history, personality, and biological measures in determining differences in the response patterns to various pharmacological agents. How should a clinician approach a pa
tient with a mixed syndrome? First of all, the possibility that the patient has a panic-agoraphobic type disorder must be excluded and that depression is not secondary to this illness; the next stage in evaluating a patient with a mixed syndrome would be to exclude that it is secondary depression or depression with anxiety symptoms. In this situation, it could be a mixed state, and clinical aspects of this were discussed in the meeting. This book will be of interest to psychiatrists, clinicians, and neuropharmacologists. It addresses issues for both the clinician and researcher regarding the importance of mixed syndromes versus single anxiety and depressive disorders in choosing appropriate pharmacological therapy. We think that it is clear that the interest in these particular clinical disorders is not only nosographical or theoretical, but is directly connected to both daily clinical practice and research.

Giorgio Racagni Enrico Smeraldi (more…)