Differences in individual responses to psychopharmacological therapy may be assumed to be phenotypical indicators of distinct underlying pathogenetic dis­orders if it is also certain that these differences are not reflecting pharmacokinetic factors. This assumption has been the basis of many significant efforts to verify whether patients who do and do not respond to various antidepressants or lithium salts can be classified into actually distinct subgroups of the major affective dis­orders. As far as lithium therapy is concerned, the consensus is that lithium responders have more relatives with major affective disorders than do nonresponders, thus suggesting that familial factors are important in distinguishing between the two subgroups (11,15). The differences between the two, however, do not appear to be limited to this factor alone. We are beginning to gather evidence (even though further studies will be required) that lithium nonresponders appear to be more likely to be high urinary MHPG excretors and to have ventricular enlargement; further, they are more likely to have had a late disease onset, a history of delusional depression, suicidal behavior, short episode cycling, and drug-induced mood switches (11,17,43,46). In addition, they seem to have qualitatively distinct pat­terns of response to tricyclic antidepressants (45). We compared the outcome to lithium prophylaxis of 14 definitely anxious depressive patients with that of 18 definitely nonanxious major depressives. The differences between the responsiveness of the two groups to long-term lithium treatment were very striking. None of the definitely anxious patients had been satisfactorily stabilized, whereas over 22% of the definitely nonanxious, 13 of the total of 18, had clearly benefited from the treatment (x 2 = 14.2; p < 0.001). Undoubtedly it would be both reasonable and easy to say that the real strength of the association between a poor lithium response and the presence of a definitely anxious pattern of depression is really weaker than that observed in this particular patient sample. Despite this, however, the results obtained still seem promising, not only from the theoretical viewpoint, but also from the clinical one. Knowing that it is possible to have a reliable early screening of major depression with different lithium treatment prospects, we can more readily plan alternative in­dividualized stabilizing programs on a rational, less hit-or-miss basis. A sizable body of evidence indicates that age at disease onset is a good index for recognizing distinct subtypes of major affective disorder. As compared to patients with early onset, those with late onset have been shown to have: higher MHPG excretion (5,13,42,53); lower alpha-2-adrenoceptor density upon platelets (43); enlarged ventricular size (14,28); a poorer response to long-term lithium therapy (45,46); fewer relatives with major affective disorders (49,55); lowered chances for manic episodes (30); an increased recurrence rate (56); and, when bipolar, higher chances for drug-induced switches into mania (17). In view of the above, it seemed worthwhile to us to explore whether there is a relationship between age at onset and definite anxiety in major depression. Among the 88 patients for whom it was possible to securely ascertain age at onset, those classified as definitely anxious had their first depressive episode later than those who were definitely nonanxious (39.8 ± 11.9 vs. 33.5 ± 12 years; Student Mest = 2.41, p < 0.02). Further, the dichotomy between early and late onset patients (cut-off age: 40 years) provided a satisfactory basis for distinguishing between major depressives with anxiety symptoms from those without anxiety. As many as 27 of the 35 late onset patients and only 22 of the 49 early onset patients were anxious (X 2 = 8.7; p < 0.003). These results do not appear to be mere indirect effects of age or polarity: the anxious and nonanxious major depressives were of comparable age (51.5 ± 10.3 vs. 50.3 ± 11.1 years), and there was an analogous incidence of bipolar disorders among them (34% and 53%, respectively; x 2 = 3.07, p = NS). Delusions On the whole, research on delusional depression strongly points to the pos­sibility that this term actually does denote and circumscribe a specific subtype of the major affective disorders. This not only is characterized by extremely virulent symptoms (evidence compatible with the hypothesis of a severity con­tinuum in depression), but also by specific biological and pharmacological fea­tures. As compared to nondelusional depressives, those with delusions not only are at higher risk for suicidal behavior (40), but also have greater chance for both abnormal dilation of the lateral cerebral ventricles (28,51) and a dysfunction of hypothalamic-pituitary-adrenal axis activity (16). Further, delusional depres­sives show a poor response to tricyclic antidepressants (TAD) given alone, benefit from TAD neuroleptics cotherapies or electroconvulsive therapy (22,36,37), and do not become adequately stabilized by lithium therapy (46). This picture of delusional depression aroused our interest in attempting to determine whether definite anxiety and delusion in major depressives are inter­twined phenomena. In the group of 68 patients studied, only 3 of the 31 (9.6%) nonanxious depressives were also unerringly delusional. Clear delusional states, however, were found in 12 of the 37 (32%) definitely anxious patients (x 2 = 5.08, p = 0.023). In the latter group, the relative risk of mood-congruent delusions was 4.5 times higher than that in the former. These data clearly indicate that the anxiety-delusions association in major depression is not merely fortuitous, despite the high incidence of false positives (37%), which is at least partially secondary to an overrepresentation of anxious versus delusional cases in the total study group.

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