These findings are in keeping with a good deal of emerging recent literature. The view that tricyclics are particularly effective in endogenous depression has an impressive lineage (20), going back as early as the initial open study by Kuhn (14) and the first controlled trial by Ball and Kiloh (1). However, a critical look at the controlled trials published in the 1960s suggests that, although the effect may have been a little better in endogenous depressives, there was evidence of benefit in neurotic depressives (20). Certainly there have been many controlled trials, including a number of relatively early ones in which tricyclics would have to be regarded as superior to placebo in samples characterized as neurotic or reactive (1,3,5,38,40). Part of the problem may lie in the failure to characterize further the neurotic depressives who themselves are heterogeneous, as our early cluster analytic study showed (18). More recent findings regarding delusional depression also present a problem for the earlier view. Although they are associated with psychotic/endogenous depression, there have been a number of reports indicating that delusions predict a poor response to tricyclic antidepressants (20). Depressives with delusions ap­pear to do much better with ЕСТ . It would appear that the most severe endog­enous or psychotic depressives do not respond very well to tricyclics. If anything, there is a curvilinear relationship in which the best response is shown by patients with the endogenous symptom pattern but moderate severity. Rao and Coppen (27) found the best response to amitriptyline in patients with scores in the middle range on the Newcastle Scale for endogenous depression. Other recent studies have failed to sustain with any strength the earlier views of selective response to MAO inhibitors. Ravaris et al. (28) recently found only weak differences between amitriptyline and phenelzine in symptom effects on anxious depressives. Davidson et al. (4) have analyzed the items of the Newcastle Anxiety Depression Diagnostic Index in relation to response to MAO inhibitors and tricyclics using data from several studies. The findings were mixed and inconsistent; in men, the depressed responded better than the anxious to MAO inhibitors. Liebowitz et al. (15) have, however, found some evidence that patients with reversed functional shift do better on phenelzine than imipramine. There is increasing evidence that tricyclics are superior to placebo in anxiety states and anxious depression. A tricyclic was found superior to placebo in ago­raphobics by Sheehan et al. (34) and Zitrin et al. (41) Marks (16) has reviewed a number of studies showing tricyclics superior to placebo in agoraphobics. Two important studies including a spectrum of anxious and depressed patients have not received the attention they deserve. Johnstone et al. (9) treated such patients with amitriptyline, diazepam, or placebo. Amitriptyline was consistently superior to placebo, whereas diazepam showed only weak effects, even in patients with predominant anxiety. Kahn et al. (10) carried out a similar study with imipra­mine, chlordiazepoxide, and placebo with similar findings.
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The analyses reported here demonstrate that methodological approaches are critical to our eventual understanding of a possible relationship between MDD and PD. The two approaches taken by Crowe et al. (6), Noyes et al. (15), and Leckman et al. (12) differ in their use of the primary/secondary distinction. From the work of Crowe, and Noyes and colleagues, it is clear that there is not an elevated risk of chronologically primary MDD in families of probands with chronologically primary PD. However, from the work of Leckman et al. and others (12,19) and from the results reported here it is clear that the rate of MDD (without regard to whether it is primary or secondary) is significantly elevated in families of both MDD and PD probands. What is not clear from the data presented here is whether that increased rate of MDD is among all relatives of PD or agoraphobic probands or whether it occurs only in those families where the proband had a diagnosis of MDD. Leckman et al. (12) reported that there was a significant difference between relatives of MDD versus MDD + PD pro­bands. Crowe et al. (6) and Noyes et al. (15) also reported that the rate of secondary depression was elevated among relatives of PD probands with secondary depres­sion, but the data do not allow a direct comparison to the results of Leckman et al. (12). Nevertheless, it appears that the co-occurrence of MDD and PD within the same individual is an important predictive factor for MDD among the relatives regardless of whether PD or MDD is the chronologically primary disorder. Clinical studies have examined patients with both MDD and PD and have shown differences when compared to patients with MDD alone. Van Valkenburg et al. (20) showed such patients to have the poorest outcome on follow-up. They were also the patients who responded least favorably to tricyclic antidepressant intervention. Nutzinger and Zapotoczky (16) also demonstrated that individuals with "cardiac phobia" who had a secondary depression were more likely to be ill at follow-up. Phenomenological studies have suggested that the episodes of depression that occur together with panic disorder may be somewhat unique. Vitone and Uhde (21) found that patients with both panic and depression were more likely to have episodes of severe depression with melancholic features. However, the episodes of depression tended to be shorter, with only 24% of patients having depressive episodes lasting more than 2 weeks. Given these findings and the data reported in this study, it appears that in­dividuals with both PD and MDD may have a unique syndrome when compared to individuals with only MDD or PD. In order to determine if this is the case, additional phenomenological, biolog­ical, and pharmacological studies are needed in which patients with MDD alone, PD alone, PD + MDD, and MDD + PD are studied together with their families. It must be emphasized that in future studies particular attention needs to be paid to how diagnostic assessments are made and reported. Reporting only pri­mary diagnoses can obscure important information. On the other hand, reporting only rates of diagnosis can also be misleading. All relevant diagnoses of each individual need to be reported in such a way so that it is possible to determine whether relatives have the same diagnostic profile as the probands.

The mean VBR for our patients was 6.3 ± 3.9, significantly higher than that of the age- and sex-matched controls (4.5 ± 2.6) (student Mest = 2.8; p < 0.01). Since VBR was positively correlated with the controls’ ages (r = 0.53; p < 0.01), any patient’s age-corrected VBR exceeding the age-corrected mean VBR of con­trol subjects by more than 2 standard deviations was considered abnormal. Ac­cording to this criterion, 16 patients (26%) had abnormally large cerebral ven­tricles. The incidence of ventricular enlargement in major depressives with and with­out anxiety proved to be significantly different. Eleven of the 29 anxious de­pressives (38%) but only 5 of the 33 nonanxious depressives (15%) had dilated cerebral ventricles (x 2 - 4.03; p = 0.04). Thus, in our sample, the likelihood of a patient with cerebral ventricular enlargement having concurrent marked symptoms of anxiety during depressive episodes was more than three times as high as that of one with normal ventricles (odds ratio = 3.42). To the best of our knowledge, this is the first time a relationship between anxiety and CT scan evidence of brain atrophy in major depression has been reported. However, in the only available previous report on this subject, Jacoby and Levy (12) found that depressed patients with enlarged ventricles were less anxious than those with normal ones. Their sample was entirely composed of aged individuals (mean age 73.2 years; age range 63-86 years) who were clinically depressed, but whose depressions were not operationally defined. Furthermore, the definition of ventricular dilation was a subjective one and did not take any normative data into account. Finally, the clinical rating of anxiety was made on the basis of the episode at the time of the study, so that situational, episodic anxiety was not distinguished from a consistent symptomatological pattern of the patients’ depressive episodes. All these factors make it difficult to interpret the results of the Jacoby and Levy study and impossible to compare them to our own. Although additional studies are needed to draw any definite conclusions from the present results, they warrant comment. The higher incidence of ventricular enlargement in the major depressions that usually are associated with anxiety symptoms suggests that the clinical distinction between anxious and nonanxious depressives may actually reflect major differ­ences in the underlying biological characteristics of these patients. Moreover, the finding of a morphological brain abnormality in patients with anxious depression would support the working hypothesis that the presence of anxiety symptoms may mark the more severe forms of major depressive illness. It is important to stress that affective patients with cerebral ventricular en­largement and those with definite anxious symptomatology have many common clinical and biological characteristics. Clinical features previously found to be associated with ventricular enlargement in major affective disorders, such as late age at onset (5,11,26), past history of delusional symptoms (11,25,26), suicidal tendencies (11,15), and poor response to long-term lithium treatment (11,22,26), also seem to be overrepresented in patients whose depressive episodes consistently show concurrent marked anxiety (Sacchetti et al., this volume). This pattern seems to strengthen the observed direct relationship between anxiety and ven­tricular dilation and, more importantly, strongly suggests that anxiety symptoms constitute part of the clinical-biological picture of a specific subtype of affective disorder, closely resembling that of the early clinical descriptions of the so-called involutional melancholia (14). This was defined as a depression of the later years, with prominent anxiety, frequent delusional symptoms, and high suicide proneness, a disorder for which an organic basis always had been suspected. Apart from the question of whether this affective subtype merits nosological autonomy (it is not given in recent references such as DSM-III), involutional melancholia could be conceived as the most extreme form (as far as age at onset, clinical picture, and severity are concerned) of a specific subtype of affective disorder accompanied by cerebro-morphological abnormalities. At present, the etiological role of organic brain disease in affective disorders and the issue of whether cerebral ventricular enlargement actually reflects such a disease still await clarification. We know that ventricular dilation is a nonspecific abnormality present in such diverse conditions as schizophrenia (21), affective disorders (11-13,18,19,23, 25,26), dementias (7), personality disorders (26), and even in normal aging (2). This abnormality, however, may well be the "final common pathway" of different organic brain processes (still unknown) that may be specific to each clinical condition in which enlargement is demonstrable. Should the CT finding of ventricular enlargement in major depression definitely be proven to demonstrate a neuropathological process, we will have identified a possible causal factor for a specific subtype of depression, with concurrent marked anxiety and a severe clinical and prognostic picture. In this case, the Kraepelinian hypothesis of brain organicity relative to involutional melancholia would be given new experimental support after a century, thanks to the advent of novel brain imaging techniques and their application to psychiatric research.

Department of Clinical Psychiatry, Laboratory of Clinical Neuropsychopharmacology, University of Milan, 20122 Milan, Italy
Depression and anxiety are phenomena frequently experienced by the elderly. The use of antidepressant, anxiolytic, and hypnotic drugs is an important indication of this, since its frequency is extremely high just past the age of 65 (especially in women), and the suicide rate reaches its peak at about 70 years (5). Very often these phenomena are mixed in the form usually termed anxious-depressive syndrome, in which a psychopathological state is defined in purely phenomenological terms and in which the anxious and depressive components are mixed, with more or less pronounced somatic complaints and insomnia. In late life, this syndrome is characterized by a higher etiopathogenetic het­erogeneity, but also by a more evident complexity in semiological, diagnostic, nosographic, and, accordingly, therapeutic terms. From an etiopathogenetic point of view, in the elderly, depression and anxiety generally arise from a mixture of sociogenetic, psychogenetic, and biological factors difficult to elucidate. Therefore, any attempt to perform a subdivision in nosographic terms of the two major entities, the endogenous depressive forms and the reactive forms, using, for example, the Newcastle Inventory Scale (9), is virtually impossible, since there is a huge imbalance in favor of the reactive type due to the burden of sociogenetic and environmental factors. From the semiological perspective, the symptoms of both the anxious and depressive series are variable, often more or less partially masked, generally anomalous versus those observed in the adult. Thoughts often appear to be focused on the indi­vidual’s objective physical troubles, in the sense of minus or of various functional changes (reduced deambulation, prostatic hypertrophy, aches, etc.), with a very intense affective participation. These peculiar ideoaffective processes could be the single "signs" of a latent depressive situation and the diagnostic difficulties of these forms arise, indeed, from these phenomenological peculiarities. From the therapeutic point of view, functional impairment at cerebral and extracerebral levels, as well as changes in some physiological parameters regulating the kinetic disposition of the various compounds into the body, make the use of psychotropic drugs particularly complex. (more…)

In this study of elderly community residents aged 65 and over, no evidence emerged that levels of anxiety associated with case levels of depressive illness affected outcome when measured crudely in terms of death, being well (having no significant psychiatric symptoms), and being psychiatrically ill three years later. Only a tiny proportion of the subjects appeared to receive antidepressant medication during this time.
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Looking at our present data we can see the total lod-score values as a function of THETA for the hypotheses of a linkage with HLA В locus and A and В loci together (haplotypes). Figure 1 shows the findings that we observed for all our families tested. The
two curves each represent the sum of the lod-scores at the given THETA values obtained by the various families represented in the sample, so that the two curves are a graphical representation of total mean values. It should be noted that both the hypotheses of random assortment of the two loci (THETA = 0.5) and complete identity (THETA = 0.0) are unlikely, whereas the best lod-scores are comprised in a range of THETA values from 1.5 to 3.0, therefore indicating a mild to moderate physical genetic distance of the two loci (MDI and HLA) on the same chromosome. Even though numerical analysis does not offer exciting results (we lie in a sort of uncertainty zone where linkage could neither be strongly confirmed nor be ruled out), it can be seen that the hypothesis of a linkage with the В locus is better than with the haplotypic structure. Nevertheless, peaks of the two curves, corresponding to a kind of maximization of the test, are not too far from each other, thus corroborating a biological re­semblance of the two different hypotheses. We are still using a model of para-metrical analysis in which parameters are the genetic determinants of the marker locus and of the susceptibility (=MDI) locus. Consequently, when we look at the results obtainable for single families, we can observe a more complex pattern: The different behavior of the three families presented in Fig. 2 reveals the presence of heterogeneity that in this particular case is mainly, or exclusively, genetic in origin since it is based only on genetic parameters (such as gene frequency, penetrance variability). The exclusion of families with the worst results (for example, the dotted line family) may improve the total lod-score because it is likely that such families behave as having no linkage with the HLA complex. Moreover, among the various parameters we used, penetrance reveals the higher influence on linkage estimates. In fact, we know that a widely accepted way of measuring the penetrance defect of a complex character is to correlate the penetrance defect itself with the variability in age at onset distribution and to use this distribution for deriving, in a function too complex for description here, an age-corrected weight of every subject involved in the analysis (4). Figure 3 describes the effect of varying the ranges of age at onset distribution over the THETA estimates and also over the Log-Likelihoods values that represent the absolute probabilistic value for a given family. Thus, we must pay careful attention to treating and modifying the genetic parameters, and it should be remembered that the linkage models we used were originally built to study the simplest Mendelian all-or-none traits. When we modify these models to analyze non-Mendelian characters, methodological problems, as we pointed out earlier, may lower the reliability of the lod-score method. Finally, we used only data and genetic parameters strictly derived by experi­mental approaches without any modified simplification in order to obtain better results. In spite of all this, a comparison of our experimental data with the simulation data of Kruger et al. (6) shows a higher level of absolute probabilistic value that can be seen as an indirect proof of the good reliability of our results (Fig. 4). (more…)