These early findings appeared promising, but thereafter the picture became much more complex. We next turned our attention to response to MAO inhib­itors. The literature on this relies very much on the concept of atypical depression, another depressive classification that overlaps with anxious depression. The first clear published description of atypical depression was in a study by West and Dally (39) working with Sargant at St. Thomas’s Hospital. Responders to iproni-azid were described as showing a syndrome that included longer illness, phobic and generalized anxiety, fatigue, evening worsening, hysterical symptoms; absence of self-reproach, of morning worsening, and of early wakening; and sometimes an impression of life-long inadequate personality, although on close examina­tion premorbid personality was nonneurotic. There have been many subse­quent papers. When we came to look over the literature we were impressed that there were three different meanings that had been used by different authors when referring to atypical depression (22). The first one was that of marked anxiety and phobic symptoms, either accompanied by depression or assumed to have some relation to an underlying depression, as indicated, for instance, by diurnal variation. This is much the same as anxious depression. It would include the influential views of Tyrer (37) that MAO inhibitors are "delayed psycho-stimulants" indicated for agoraphobia, anxiety neurosis, anergia, and mixed anxiety depressions rather than pure depressions. The second meaning is what Pollitt (25) describes as reversed functional shift, i.e., depression with a diurnal pattern of evening worsening, insomnia of early rather than late kind, or increased sleep, increased appetite and weight, all in the opposite directions to the physiological changes said to characterize endog­enous depression. In the United States Klein and colleagues (15) assigned prin­cipal importance in their selection criteria to increased sleep, increased weight, and reactivity of mood and have found some evidence that atypical depressives so defined respond better to phenelzine than to imipramine. A third usage of the term atypical depression is a wide one of nonendogenous depression in general. In the United States a systematic series of studies of MAO inhibitors has been carried out by Robinson, Nies, and Ravaris. They have derived a diagnostic index for typical and atypical depression (29) that assigns high weights for typical depression to suicidal ideation, weight loss, depressed mood, agitation, retardation, guilt, hallucinations, and nihilistic delusions; high weights for atypical depression to psychic and somatic anxiety, initial insomnia. These three meanings are separate and do not necessarily identify the same patients. We assigned a mixed sample of outpatient depressives to a wide variety of different classificatory systems (22). We examined the relationships between diagnostic systems using Cramers’ V, a nonparametric measure of association. Using separate classifications based on marked anxiety symptoms, reversed functional shift, and nonendogenous depression, we found that these three criteria related poorly, and tended to select quite different patients. We had to conclude that the concept of atypical depression was imprecise. It would be better to specify which aspect was under consideration. Our main interest was in the response to MAO inhibitors. Here previous studies have not been clear-cut. The best evidence that type of depression predicts response comes from controlled trials of phenelzine against placebo (20), among which studies in outpatients, likely to include milder, more neurotic patients, have tended to show drugs superior to placebo, whereas inpatient studies have not. There are also positive studies in phobics. In a predictor study (20), we found better response in outpatients, patients who were less severely ill, not retarded, showed an admixture of anxiety symp­toms, and scored at the atypical end of the Nies-Robinson Diagnostic Index. The earlier cluster analytic typology did not predict. However, this was an open study without placebo or tricyclic comparison groups. We therefore undertook a controlled trial in outpatient depressives (24,33). One hundred and thirty-one outpatients with depression and mixed anxiety depression were randomly assigned to 6 weeks of treatment with phenelzine rising to a dose of 60 to 75 mg daily, amitriptyline 150 mg daily, or placebo. On global measures and total severity scores, both drugs were found to be clearly superior to placebo and to much the same extent. In a predominantly neurotic sample of the type in which tricyclics have often been thought not to be useful, they appeared to be of considerable benefit. When we examined individual symptom ratings to see which symptoms were predominantly affected it was clear that both drugs had their main effects on the classical symptoms of depres­sion, including depressed mood and depressed thought content (33). On anxiety measures, effects of both drugs were quite weak. There was, however, a slightly better effect on anxiety measures from phenelzine than from amitriptyline. We classified these patients in a variety of ways, reflecting the three different concepts of atypical depression, and looked for differential drug responses. We found relatively little evidence of patient groups responding specifically to phen­elzine or amitriptyline rather than responding well to both drugs (24). We found no interactions greater than chance significance in two-way analyses of covariance between drug effects and diagnostic subtypes based either on atypical functional shift or a broad concept of nonendogenous depression. We did find a little evi­dence of interactions in subgroups based on the additional presence of anxiety, such that phenelzine produced its best effect in patients with an admixture of anxiety with their depression. However, this effect was only found with certain classifications, and amitriptyline was also clearly superior to placebo in anxious depressives, although a little less so than phenelzine. Overall, the findings of this study did not indicate that tricyclics are without value in anxious depression, when the comparison is made with placebo so that the true contribution of the drug effect can be measured. Rather they tended to suggest that tricyclics have a broad spectrum of antidepressant effects.

1. Ball, J. R., and Kiloh, L. G. (1959): A controlled trial of imipramine in treatment of depressive states. Br. Med. J., 2:52. 2. Carney, M. W. P., Roth, M., and Garside, R. F. (1965): The diagnosis of depressive syndromes and the prediction of ЕСТ response. Br. J. Psychiatry, 121:35. 3. Covi, L., Lipman, R. S., Derogatis, R., Smith, J. E., and Pattison, J. H. (1974): Drugs and group psychotherapy in neurotic depression. Am. J. Psychiatry, 131:191. 4. Davidson, J., Pelton, S., Krishnan, R. R., and Allf, B. (1986): The Newcastle anxiety depression index in relationship to the effects of MAOI and TCA drugs. J. Affective Disord., 11:51-58. 5. Friedman, A. S. (1975): Interaction of drug therapy with marital therapy in depressive patients. Arch. Gen. Psychiatry, 32:619. 6. Hamilton, M., and White, J. M. (1959): Clinical syndromes in depressive states. J. Merit. Sci., 105:985-998. 7. Hollister, L. E., Overall, J. E., Johnson, M. H., Shelton, J., KJmbell, I., and Brunse, A. (1966): Amitriptyline alone and combined with perphenazine in newly admitted depressed patients. /. Nerv. Ment. Dis., 142:460-469. 8. Hollister, L. E., Overall, J. E., Shelton, J., Pennington, V., Kimbell, I., and Johnson, M. (1967): Drug therapy of depression: Amitriptyline, perphenazine and their combination in different syndromes. Arch. Gen. Psychiatry, 17:486-493. 9. Johnstone, E. C, Cunningham Owens, D. G., Frith, C. D., McPherson, K., Dowie, C, Riley, G., and Gold, A. (1980): Neurotic illness and its response to anxiolytic and antidepressant treat­ment. Psychol. Med., 10:321-328. 10. Kahn, R. J., McNair, D. M., Lipman, R. S., Covi, L., Rickels, K., Downing, R., Fisher, S., and Frankenthaler, L. M. (1986): Imipramine and chlordiazepoxide in depressive and anxiety disorders. Arch. Gen. Psychiatry, 43:79-85. 11. Kendell, R. E. (1968): The Classification of Depressive Illnesses. Maudsley Monogr. No. 18. Oxford University Press, London. 12. Kiloh, L. G, Andrews, G, Neilson, M., and Bianchi, G. N. (1972): The relationship of the syndromes called endogenous and neurotic depression. Br. J. Psychiatry, 121:183-196. 13. Kiloh, L. G, and Garside, E. F. (1963): The independence of neurotic depression and endogenous depression. Br. J. Psychiatry, 109:451-463. 14. Kuhn, R. (1958): The treatment of depressive states with G22355 (imipramine hydrochloride). Am. J. Psychiatry, 115:459. 15. Liebowitz, M. R., Quitkin, M., Stewart, J. W., McGrath, P. J., Harrison, W., Rabkin, J., Tricamo, E., Markowitz, J. S., and Klein, D. F. (1984): Phenelzine v imipramine in atypical depression. Arch. Gen. Psychiatry, 41:669-677. 16. Marks, I. (1983): Are there anticompulsive or antiphobic drugs? Review of the evidence. Br. J. Psychiatry, 143:338-347. 17. Overall, J. E., Hollister, L. E., Johnson, M., and Pennington, V. (1966): Nosology of depression and differential response to drugs. J. Am. Med. Assoc, 195:946-948. 18. Paykel, E. S. (1971): Classification of depressed patients: A cluster analysis derived grouping. Br. J. Psychiatry, 118:275-288. 19. Paykel, E. S. (1972): Depressive typologies and response to amitriptyline. Br. J. Psychiatry, 120: 147-156. 20. Paykel, E. S. (1979): Predictors of treatment response. In: Psychopharmacology of Affective Dis­orders, edited by E. S. Paykel and A. Coppen, pp. 193-220. Oxford University Press, Oxford. 21. Paykel, E. S. (1985): The clinical interview for depression development, reliability and validity. J. Affective Disord., 9:85-96. 22. Paykel, E. S., Parker, R. R., Rowan, P. R., Rao, B. M, and Taylor, С N. (1983): Nosology of atypical depression. Psychol. Med., 13:131-139. 23. Paykel, E. S., Prusoff, B. A., and Klerman, G. L. (1971): The endogenous-neurotic continuum in depression: Rater independence and factor distributions. / Psychiatr. Res., 8:73-90. 24. Paykel, E. S., Rowan, P. R., Parker, R. R., and Bhat, A. V. (1982): Response to phenelzine and amitriptyline in sub-types of neurotic depression. Arch. Gen. Psychiatry, 39:1041-1049. 25. Pollitt, J. (1965): Depression and Its Treatment. Heinemann, London. 26. Prusoff, B. A., and Paykel, E. S. (1977): Typological prediction of responses to amitriptyline: A replication study. Int. Pharmacopsychiat., 12:153-159. 27. Rao, V. A., and Coppen, A. (1978): Classification of depression and response to amitriptyline therapy. Psychol. Med., 9:321-325. 28. Ravaris, С L., Robinson, D. S., Ives, J. O, Nies, A., and Bartlett, D. (1980): Phenelzine and amitriptyline in the treatment of depression. Arch. Gen. Psychiatry, 37:1075-1080. 29. Robinson, D. S., Nies, A., Ravaris, С L., Ives, J. O, and Lamborn, K. R. (1974): Treatment response to MAO inhibitors: Relation to depressive typology and blood platelet MAO inhibition. In: Classification and Prediction of Outcome of Depression, pp. 259-267. Schattauer-Verlag, Stuttgart. 30. Rosenthal, S. H., and Gudeman, J. E. (1967): The endogenous depressive pattern: An empirical investigation. Arch. Gen. Psychiatry, 16:241-249. 31. Rosenthal, S. H., and Gudeman, J. E. (1967): The self-pitying constellation in depression. Br. J. Psychiatry, 113:485-489. 32. Rosenthal, S. H., and Klerman, G L. (1966): Content and consistency in the endogenous depressive pattern. Br. J. Psychiatry, 112:471-484. 33. Rowan, P. R., Paykel, E. S., and Parker, R. R. (1982): Phenelzine and amitriptyline: Effects on symptoms of neurotic depression. Br. J. Psychiatry, 140:475-483. 34. Sheehan, D. V., Ballenger, J., and Jacobsen, G. (1980): Treatment of endogenous anxiety with phobic hysterical and hypochondriacal symptoms. Arch. Gen. Psychiatry, 37:51-59. 35. Sireling, L. I., Freeling, P., Paykel, E. S., and Rao, В . М . (1985): Depression in general practice: Clinical features and comparison with out-patients. Br. J. Psychiatry, 147:119-126. 36. Sireling, L. I., Paykel, E. S., Freeling, P., Rao, В . М ., and Patel, S. P. (1985): Depression in general practice: Case thresholds and diagnosis. Br. J. Psychiatry, 147:113-119. 37. Tyrer, P. (1976): Towards rational therapy with monoamine oxidase inhibitors. Br. J. Psychiatry, 128:354-360. 38. Uhlenuhuth, E. H., and Park, L. С (1964): The influence of medication (imipramine) and doctor in relieving depressed psychoneurotic patients. J. Psychiatr. Res., 2:101. 39. West, E. D., and Dally, P. J. (1959): Effects of iproniazid in depressive syndromes. Br. Med. J., 1:1491-1499. 40. Wittenborn, J. R., Plante, M., Burgess, F., and Maurer, H. (1962): A comparison of imipramine, ЕСТ and placebo in the treatment of depression. J. Nerv. Ment. Dis., 135:131-137. 41. Zitrin, С M., Klein, D. F., and Woerner, M. G. (1980): Treatment of agoraphobia with group exposure in vivo and imipramine. Arch. Gen. Psychiatry, 37:63-72.
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E. S. Paykel
Department of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, England (more…)

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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Overall these findings from the general practice study form quite a consistent picture with other emerging data. Rather than being selective drugs limited in their effect to endogenous depressives, the tricyclic antidepressants appear to be relatively broad spectrum drugs having true antidepressant effects over quite a wide range of depressive disorders. This includes neurotic depressives and anxiety depressives, and it extends much further than one might have thought into the mild range. It is only the very mildest depressives who fail to show drug/placebo differences. There may be limited differences in those who respond best based on symptom pattern, previous history, and other characteristics, but the general pattern is for tricyclic antidepressants to be of therapeutic benefit and to have a true antidepressant effect over a wide variety of patients, provided that they satisfy psychiatric criteria for depression. This applies clearly to anxious depres­sives and appears to extend well into the spectrum of anxiety disorders, although not necessarily to all such cases.

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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Further support for the view that the therapeutic effect of tricyclic antide­pressants extends well outside the classical spectrum of severe endogenous depressions comes from a study that we have recently undertaken and that is currently being analyzed. This is a placebo-controlled trial of amitriptyline in depressions presenting in general practice. We were interested in this problem because the majority of depression in Britain are treated by general practitioners, only about one in ten being referred to psychiatrists. We had undertaken earlier a study (35,36) that confirmed the general impression that such depressions are relatively mild, differing markedly in severity and quality from psychiatrically treated depressions. Even in com­parison with outpatient depressives, general practice depressives were less severely ill, less often primary, endogenous, or retarded. Most of the evidence for the efficacy of tricyclic antidepressants depends on controlled trials carried out in psychiatric outpatients or inpatients. We have, therefore, undertaken a controlled trial in general practice laying considerable emphasis on classificatory data to enable a search for those subgroups who show or fail to show drug/placebo differences. One hundred and forty-one depressives identified in general practice and sat­isfying the Research Diagnostic Criteria for major or minor depression were treated for at least 4 weeks and in most cases 6 weeks with amitriptyline or placebo double-blind. The mean doses in the fourth week and sixth week were approximately 120 mg daily. Mean initial total scores on the 17-item Hamilton Rating Scale for Depression were closely identical and were a little below 15, confirming the relative mildness of the sample. Differences started to appear surprisingly early and at 2 weeks had reached significance on this scale, although not on some others. By 6 weeks, highly significant differences had appeared on a wide variety of outcome measures with amitriptyline very impressively superior to placebo. It has sometimes been argued that the effects of tricyclic antidepressants in mildly depressed patients in general practice are largely owing to sedation and effects on sleep. We, therefore, examined a wide set of symptom ratings, partic­ularly from the Hamilton Rating Scale and the Clinical Interview for Depression (21). Individual symptom ratings showing drug/placebo differences by compar­ison of change scores using /-tests at the end of the study included, in addition to insomnia, a variety of core symptoms of depression, particularly depressed mood, guilt, pessimism, hopelessness, and depressed appearance. The effect was clearly a true antidepressant one, and it was also shown on a number of global measures. In order to examine for responsive subgroups we carried out a series of two-way analyses of covariance with initial level as covariate and using as the second factor a variety of classifications from the literature. We sought interactions that would indicate differential drug placebo differences. We analyzed six rel­atively global outcome measures and since this involved a comparatively large number of analyses, we have only accepted them for further examination when at least two of the six outcome measures in a subgroup showed significant interactions at the 5% level or better. The analyses are still in progress. So far, significant interactions have been relatively few, indicating fairly strong and consistent drug effects across most subgroups. Initial subgroups examined reflect demographic variables, history of chronicity, severity of depression, and endogenous versus neurotic depression in terms of symptoms or precipitant stress. Only in one area, severity, were there interactions, and even here they were relatively weak, only reaching 5% significance in two of the six analyses, although there were consistent effects at around the 10% level on the other out­come measures. These two subgroups, based on RDC major versus minor depression and on severity on the Hamilton Scale do show an illuminating pattern. The distinction between RDC major and minor depression depends mainly on the number of concomitant symptoms of depression that are present. For minor depressions of less severity, drug and placebo groups both improved but remained closely similar. For major depressions, starting with more severity, the amitriptyline group improved considerably more than the placebo group to reach levels at the end of the study similar to those of the minor depressives. Active drug was beneficial to major depressives but not to minor. On initial Hamilton Score, we divided the sample into three groups: the most mild, with Hamilton scores below 13; intermediate, with initial scores 13 to 15; and relatively more severe, with scores over 16. Even these patients were not very severely ill, only comparable with psychiatric outpatients. We found a very similar pattern in outcome to that based on major and minor depression. Here, however, it was only the very mildly ill patients who showed no benefit from the active drug: there were considerable drug/placebo differences for the two other patient groups, and again the effect was to produce final scores from ami­triptyline close to those of the mildly ill. There appears to be a level that the milder patients reach spontaneously, which represents improvement rather than no change and which is as much as can be achieved in 6 weeks. The effect of the active drug is to move the patients in the higher ranges of what is still a relatively mild disorder down to this level. A similar analysis has been carried out to compare patients scoring higher and lower on anxiety. So far only a single grouping has been examined, depending on total scores from the Clinical Interview for Depression, for depression and for anxiety. Using initial scores we sought to define two groups, high on anxiety but low on depression and high on depression but low on anxiety. There was, as might be expected, considerable overlap. We have carried out a similar analysis with these two groups. There were no significant interactions between this group­ing and drug effects at the end of 6 weeks.