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.

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