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Objective: Demonstration of antidepressant efficacy beyond 6 months has infrequently been addressed, and no long-term efficacy data exist for patients with chronic atypical depression. Method: Sixty patients with atypical depression (according to Columbia University criteria) of at least 2 years’ duration and who had improved with imipramine or phenelzine were stabilized for 6 months and then randomly continued the same medication or placebo for 6 months. Results: Several baseline differences suggested that patients who entered the discontinuation trial on a regimen of phenelzine were more chronically depressed than the imipramine-treated patients. Survival analysis showed a marked advantage for phenelzine relative to placebo. In addition, patients switched to placebo from phenelzine experienced a recurrence of depressive symptoms significantly more often than patients switched to placebo from imipramine. Patients maintained with imipramine did not have lower relapse rates than those switched from imipramine to placebo. Recurrence rates were 23% for patients maintained on a regimen of phenelzine, 41% for those maintained on a regimen of imipramine, 47% for those switched from imipramine to placebo, and 87% for placebo-treated patients originally treated with phenelzine. Conclusions: Patients with chronic atypical depression are at high risk of recurrence if phenelzine is withdrawn 6 months after initial improvement. Similar findings were not demonstrated for imipramine; this replicates acute trials demonstrating imipramine’s relative ineffectiveness in patients with atypical depression. Differences in recurrence rates after the switch to placebo from phenelzine and imipramine could be due to the two drugs’ different mechanisms of action or to baseline differences in the two populations. (Am J Psychiatry 1997; 154:31‐36)

Although antidepressants have been found to be superior to placebo in 12 of 14 studies, the relationship between improvement in the depressive diathesis and bulimia is unclear. In this study, the efficacy of placebo, imipramine, and phenelzine is examined in patients comor-bid for atypical depression and bulimia. Greater improvement was observed for both depressive and bulimic symptoms with phenelzine than with either imipramine or placebo. Consistent with its poor ant/depressant effects in atypical depression, imipramine seemed to have minimal efficacy for the bulimic symptoms of atypical depressives. These data suggest that the presence of bulimia does not alter the treatment response of atypically depressed patients. Furthermore, the data may suggest a link between depression and bulimia in atypical depressives. Demonstrating a statistical difference with a small sample suggests the effect size is robust, however conclusions are limited by a small sample size. © 1994 by John Wiley & Sons, Inc.

We summarise a series of studies using a MAOI to help establish the validity of a subgroup of depressives referred to as atypical depressives. Patients with reactive mood meeting DSM-III criteria for depressive illness who had associated atypical features (which include hyperphagia, hypersomnolence, leaden paralysis, and rejection sensitivity) were randomised to imipramine, phenelzine and placebo. Non-responders were crossed over, and in all there were over 400 patient trials. Phenelzine consistently was found to be superior to imipramine. Only in trials which included patients lacking atypical, vegetative symptoms was imipramine found to equal phenelzine. We conclude that the researcher and the clinician should consider the relevance of the atypical depressive syndrome.

Objective: The authors ‘ goal was to analyze the acute phase ofantidepressant drug treatment to identify placebo responses. Method: Patients rated as improved after 6 weeks of doubleblind treatment with imipramine or phenelzine were followed for an additional 6 weeks of double-blind treatment. Initial responses were classified according to the speed of improvement (abrupt or gradual), the persistence or nonpersistence of improvement, and the timing ofimprovement (early or late onset). Results: It was predicted that patients with nonpersistent, abrupt responses to the drugs were actually experiencing a placebo response and would have the worst prognosis. In fact, this group accounted for a disproportionate number of the relapses. Nonpersistent responders to a drug had a 23. 7% relapse rate, but persistent responders had only a 9.0% relapse rate, a significant difference. Conclusions: The authors conclude that a significant proportion of relapses within the first 6 weeks of treatment with an active drug are not related to loss of a true drug effect. Rather, some are related to loss of nonspecific placebo effects, and abrupt nonpersistent responses during drug treatment are most likely the result ofplacebo effects. (AmJ Psychiatry 1993; 150:566-570)

Thirty-nine depressed outpatients meeting DSM-III criteria for nonmelancholic major depression or dysthymic disorder were treated with 16 weekly individual cognitive therapy sessions. Prior to treatment, they completed the Beck Depression Inventory, the Hopelessness Scale, and the Dysfunctional Attitudes Scale. Independent of knowledge of outcome, the authors chose from these scales items indicating demoralization, that is, that patients perceived their ability to positively affect their own future as too likely to be ineffectual to warrant efforts at change. After cognitive therapy, 20 patients were considered responders (51%) although three quickly relapsed (44% responded and maintained). Nonresponders had significantly higher pretreatment demoralization scores than did responders. These results suggest that high levels of demoralization may predict poor response of depression to cognitive therapy, although the small sample size precluded differentiation of demoralization from hopelessness. Since Beck introduced cognitive therapy (Beck, 1972) numerous reports support its effectiveness (Rush, Beck, Kovacs, & Hollon, 1977; McClean & Hakstian, 1979; Murphy, Simons, Wetzel, & Lustman, 1984; Blackburn, Bishop, Glen, Whalley, & Christie, 1981; Elkin et al., 1989). Several authors have reported that cognitive therapy is more effective for patients with less pathological scores on the Dysfunctional Attitudes Scale (DAS) (Weissman & Beck, 1978) or Self- Control Scale (Rosenbaum, 1980) than those with higher scores (Keller, 1983; Simons, Murphy, Levine, & Wetzel, 1986; Sotsky, et at, 1991; Murphy et al., 1984). This is counterintuitive, since cognitive therapy was evolved to correct dysfunctional attitudes and help patients attain mastery. Thus, deeply ingrained dysfunctional attitudes may not be effectively challenged by short-term cognitive therapy .while patients who feel their lives are not under their own control may not do the homework or may only "go through the motions." Neimeyer and Weiss (1990) have recently reported attributional style to predict outcome. These authors investigated 10 weeks of group cognitive therapy and group interpersonal psychotherapy as the treatment for 111 depressed outpatients. They report that higher pretreatment severity scores on the Hamilton Rating Scale for Depression (Hamilton, 1960) and the Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) accounted for 49% of the variance in outcome scores. Once baseline severity was accounted for in a stepwise regression analysis, cognitive attributional style accounted for an additional 12% of the variance in final depression scores. Specifically, patients who identified very general causes for negative outcomes, but also attributed positive outcomes to only a few sources were more depressed following treatment than were patients who attributed negative outcomes to only a few sources or who found many sources of positive outcomes in their lives. This finding applied whether the treatment was cognitive or interpersonal group psychotherapy. Our own experience suggested that cognitive therapy often activated inert, immobile patients. Thus, it seemed that patients who had become "demoralized" might be the best candidates. We use the term "demoralized" to describe patients who are distressed by their perception of being unable or unlikely to make positive changes in their lives. Demoralization is evidenced by such statements as "things won't work out," "why try anyway," "everything is too much of an effort" and "I am unable to accomplish my goals." These patients have lost motivation, feeling they have been beaten down too many times and do not want to risk further hurt or discouragement. There is a belief in personal failure, such that the demoralized person does not want to risk that failure again. The usual questionnaires utilized in cognitive therapy were scrutinized for items which might reflect demoralization. …

Fifty outpatients with mild, chronic, mood-reactive depression whose mood improved markedly after a 10-day single-blind placebo trial were randomly assigned in a double-blind design either to have their placebo medication discontinued or to have it maintained for an additional 6 weeks. Half of the patients in each condition relapsed within 6 weeks, indicating that pill-taking itself does not influence maintenance of placebo response. Placebo response was more likely to be maintained in patients who were currently married. At the end of 3 months, the overall relapse rate was 58%. The authors raise questions about the utility of the initial 10-day placebo washout in antidepressant clinical trials, and they discuss limits on the generalizability of their findings.

Of 60 depressed alcoholics who completed an open trial of imipramine, 27 (45%) responded with improvement in both mood and drinking behavior, and eight (13%) responded after further dosage increases or treatment with disulfiram. In a subsequent 6-month, randomized discontinuation trial, four of 13 subjects (31%) relapsed during imipramine treatment and seven of 10 (70%) relapsed while taking placebo. This suggests a potential treatment approach for a high-risk subgroup of alcoholics.

OBJECTIVE: This study sought to determine what proportion of relapses during continuation therapy with antidepressants can be attributed to loss of nonspecific placebo effects while the patients are taking the drugs. METHOD: Depressed patients were studied over a 12-week period. One hundred sixty-four patients were randomly assigned to placebo, 174 to imipramine, and 169 to phenelzine. At 6 weeks 35 were judged to be responders to placebo, 70 to imipramine, and 96 to phenelzine. These patients continued their double-blind treatment for weeks 7-12. RESULTS: Thirty-one percent of the patients who were taking placebo, approximately 12% who were taking imipramine, and approximately 9% who were taking phenelzine relapsed in the 7- to 12-week phase. Two different methods of estimating relapses suggested that during the first 3 months of treatment, a large percentage of the relapses of patients taking drugs was attributable to the loss of nonspecific placebo effects rather than true drug effects. CONCLUSIONS: A considerable proportion of relapses in the first 3 months of treatment with antidepressants appears to be due to loss of placebo effects. These clinically relevant data may be used to encourage patients who relapse during this period, and who erroneously conclude that anti-depressant effects are temporary, to try another medication.

The objective of our study was to demonstrate that additional antidepressant benefit occurs between weeks 4 and 6 in adult outpatients, even when dose is not increased. Response between weeks 4 and 6 was studied among depressed outpatients randomly assigned to imipramine, phenelzine, or placebo under double-blind conditions. Patients were selected for analysis only if they did not have a dose increase after the start of the fourth week of treatment (day 22). Eighty-eight patients met this condition. Conditional probability analysis was performed. Nonresponders to 4 weeks (28 days) of treatment had a significantly greater likelihood of responding by week 6 if they were on phenelzine rather than placebo. The same is probably true for patients on imipramine. In research and clinical care, 4 weeks is too short a trial of phenelzine to conclude a lack of efficacy. Four weeks is probably also too short a trial of imipramine.

We reanalyzed data from a larger, previously published study in order to directly address whether very chronically depressed patients could benefit from antidepressant medications. This study entered 598 depressed patients into a study randomizing patients to 6 weeks of double-blind treatment with imipramine, phenelzine, or placebo. Patients were assessed for chronicity on a four-point scale from "mostly well" to "virtually always depressed." The current analyses include only the 153 study completers who were rated as "virtually always depressed." In these patients, imipramine was effective for significantly more patients than was placebo (22 [46%] of 48 responding to imipramine vs. 9 [17%] of 52 responding to placebo; chi 2 = 9.50; p = 0.002), whereas phenelzine was significantly more effective than imipramine (37 [70%] of 53 responding to phenelzine; chi 2 = 5.96; p = .015). Patients with mild depression, early onset, or histories of panic attacks did not have substantially different outcomes than patients without these characteristics. These findings suggest that some chronically depressed patients may be good candidates for treatment with antidepressant medication. Because the majority (80%) of the sample met Columbia criteria for definite or probable atypical depression, too few chronic depressives were available to evaluate separately antidepressant efficacy in chronically depressed outpatients who did not have atypical depression. Hence, these results may be applicable only to patients with atypical depression.

Data for 401 depressed outpatients with mood reactivity who participated in a randomized trial comparing placebo, imipramine, and phenelzine were analyzed for predictors of differential response by stepwise multiple regression techniques. Features of the Columbia criteria for atypical depression including oversleeping, overeating, severe anergy, and pathologic rejection sensitivity were each predictive of a poorer response to imipramine than to phenelzine only when compared to those patients with none of the features. These features were not additive in their contribution to differential outcome. Lack of endogenous features was not predictive of a differential drug treatment response. Compared with patients who have no symptoms of atypical depression, patients with any of the four features had an inferior imipramine response rather than a superior phenelzine response. These analyses indicate that the clear differential responsivity to medication treatment in atypical depression is not simply related to any one defining symptom and that further correlates of this apparent biological heterogeneity need to be explored.

We employed a study design that permitted a double-blind 12-week contrast of imipramine hydrochloride and phenelzine sulfate therapies in patients who met Columbia University criteria for atypical depression and were unresponsive to 7 weeks of treatment with placebo. These patients were found to benefit selectively from therapy with monoamine oxidase inhibitors compared with tricyclic drug therapy. This supports our observation about treatment response in depressed patients with reversed vegetative features. The design we utilized in this study has not previously been reported, to our knowledge. It was hypothesized that it would offer the advantage of the removal of a portion of placebo responders and serve to replicate our original findings. Treatment response to therapy with both imipramine and pheneizine in placebo nonresponders was uniformly lower (roughly 20% less than corresponding rates for patients who did not participate in the initial 6-week placebo trial). This is consistent with the view that the lower response rates were a result of the removal of some "placebo" responders in the drug groups. We think this is a useful design that should be considered in all studies of placebo and two active treatment regimens.

In an initial study with 120 patients with reactive mood and associated atypical symptoms, phenelzine sulfate was superior to imipramine hydrochloride and placebo. Since their response to phenelzine appears to be unique, this suggests that atypical depression may be a distinct subgroup of unipolar depressive illness. Unexpectedly, the benefit of antidepressants was limited to patients who also had spontaneous panic attacks. To help establish the validity of this syndrome, a new sample of 90 atypical depressives was studied. The clinical and demographic characteristics of the original and replication sample were virtually identical at baseline. In addition, the treatment response with either placebo, imipramine, or phenelzine was also indistinguishable in the two patient groups. The outcome in the replication study supports the hypothesis that this may be a distinct unipolar depressive subgroup. In the replication sample, a history of panic attacks did not appear to be a relevant predictor. We discuss the explanations for this discrepancy in the two patient samples.

Social functioning was assessed in 189 nonmelancholically depressed outpatients. Patients were then treated for 6 weeks in a double-blind trial of phenelzine, imipramine, or placebo and functioning was reassessed. Before treatment, younger, more severely depressed, more chronically depressed patients and those with a DSM-III diagnosis of major depression plus dysthymic disorder were more functionally impaired than patients without these characteristics. Chronically depressed patients who responded to treatment reported significantly improved functioning while nonresponders did not. These results suggest that for some chronically depressed patients, impaired functioning results at least partly from the Axis I mood disorder instead of being entirely attributable to Axis II character pathology.

• One hundred nineteen patients who met specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 71% with phenelzine, 50% with imipramine, and 28% with placebo. Phenelzine was widely superior to placebo and also showed superiority to imipramine. Phenelzine superiority appeared even greater after an additional six-week continuation phase. Imipramine was only moderately effective in this atypical depressive sample. Unexpectedly, the superiority of either phenelzine or imipramine to placebo was largely confined to patients in subsets of the study sample who were prospectively judged to also have a history of spontaneous panic attacks and/or show hysteroid dysphoric features. This is consonant with some but not other recent findings and requires replication. Overall, the concept of atypical depression as a subtype that is preferentially responsive to monoamine oxidase inhibitors is supported.

The incidence of major side effects of phenelzine and tranylcypromine is compared with that of imipramine and placebo medication in depressed outpatients. Psychiatric notes in the charts of 198 patients were reviewed. Based on clinical experience and literature review, 14 side effects were selected for study because of serious medical risk or subjective discomfort great enough to require drug discontinuation. Significant differences in risk for major side effects, as well as distinctive side effect profiles for each drug, were found. More side effects occurred on phenelzine, but these tended not to lead to drug discontinuation more often than with tranylcypromine, nor were they accounted for by differences in age, sex, diagnosis, or duration of treatment.

Although the electrocardiographic effects of the tricyclic antidepressants have been extensively investigated, there are fewer data on the effects of monoamine oxidase inhibitors and tetracyclics on cardiac conduction. This study used high speed recordings of the electrocardiogram to investigate the cardiographic effects of phenelzine and mianserin and to compare these to the effects of imipramine, amitriptyline, and placebo. Phenelzine caused significant slowing of the heart rate, while mianserin showed little effect on heart rate compared to the increases in rate seen with tricyclics. In clinically effective doses, neither phenelzine nor mianserin caused changes in conduction, while both tricyclics studied caused the expected prolongation of conduction. These data suggest that phenelzine and mianserin deserve further study in patients with disease of the cardiac system as they may be less likely to cause heart block in these patients.

From a review of the clinical charts of 198 depressed outpatients, information was extracted on common major treatment emergent side effects associated with phenelzine, tranylcypromine, and imipramine. These included hypertensive reactions, severe orthostatic hypotension, hypomania, significant weight gain, sexual dysfunction, and a residual category of multiple side effects which together culminated in drug discontinuation. In this report, frequency of their occurrence for each drug, level of severity, relation to dose and treatment duration, and physician response at the time the side effect was recorded are described. In addition, procedures found useful in the clinical management of these side effects are discussed.

• Sixty patients meeting specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 67% with phenelzine, 43% with imipramine, and 29% with placebo. At week 6, phenelzine was superior to placebo on many measures, while the superiority of imipramine to placebo was confined to several variables. Phenelzine was superior to imipramine on the interpersonal sensitivity and paranola factors of the 90-Item Hopkins Symptom Checklist, with trends toward superiority on several other measures, while imipramine was not differentially superior on any measure. Atypical depressive patients with a history of spontaneous panic attacks and hysteroid dysphoric patients both showed extremely low rates of response to placebo and high rates of response to phenelzine. Conversely, those without panic or hysteroid dysphoric features responded equally to all three treatments. Responders to phenelzine also had greater platelet monoamine oxidase inhibition while receiving drug therapy than did nonresponders. Completion of the 120-patient sample will allow more detailed analyses.