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.

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