Prophylactic efficacy of phenelzine and imipramine in chronic atypical depression: likelihood of recurrence on discontinuation after 6 months' remission.

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 CONCLUSIONS: Patients with chronic atypical depression are at high risk of recurrence if phenelzine is withdrawn 6 months after initial improvement.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.

Duration of antidepressant trials: clinical and research implications.

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.

A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives.

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 comorbid 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 antidepressant 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.

Chronic depression: response to placebo, imipramine, and phenelzine.

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.

Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo.

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.

Imipramine treatment of alcoholism with comorbid depression.

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.

Loss of drug effects during continuation therapy.

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.

Further evidence that a placebo response to antidepressants can be identified.

OBJECTIVE: The authors' goal was to analyze the acute phase of antidepressant drug treatment to identify placebo responses. METHOD: Patients rated as improved after 6 weeks of double-blind 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 of improvement (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 of placebo effects.

Predictive value of symptoms of atypical depression for differential drug treatment outcome.

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.

Response to phenelzine and imipramine in placebo nonresponders with atypical depression. A new application of the crossover design.

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.

Heterogeneity of clinical response during placebo treatment.

OBJECTIVE: The authors attempted to identify different patterns of improvement among patients receiving placebo during clinical trials. It was hypothesized that patients who improved abruptly would differ from patients whose improvement was gradual in that they would tend to improve earlier and would tend to have less persistent improvement. METHOD: The subjects were 144 patients who met the DSM-III criteria for depressive illness and were randomly assigned to placebo medication in four double-blind antidepressant drug trials. All studies lasted 6 weeks. Mood change was rated each week on a 7-point scale; a rating of 1 or 2 was considered an indication of improvement. Improvement was judged to be abrupt if the first score of 1 or 2 was immediately preceded by a score of 4 or worse, and it was classified as gradual if the first score of 1 or 2 was preceded by a score of 3 in at least 1 week. Improvement was considered persistent if a score of 1 or 2 was not followed by a score of 3 or worse in any subsequent week. RESULTS: Of the 144 patients, 72 showed clinical improvement during at least one weekly visit; 33 improved abruptly and 39 improved gradually. The abrupt improvements occurred significantly earlier in the trial and were less likely to persist than the gradual improvements regardless of when they occurred. CONCLUSIONS: These data suggest that among patients receiving placebo abrupt improvements are a form of placebo response and gradual responses may be the result of spontaneous remission. These preliminary observations require validation.

Different types of placebo response in patients receiving antidepressants.

OBJECTIVE: The authors studied the responses of drug-treated patients in an attempt to validate observations about abrupt and gradual improvements in patients receiving placebo. Since previous data suggested that in the first 2 weeks of antidepressant treatment specific drug effects are unlikely, the authors hypothesized that this improvement is a placebo effect. Therefore, in the first 2 weeks of antidepressant treatment abrupt and gradual improvements should have the characteristics of their placebo counterparts. METHOD: The subjects were 263 patients in controlled antidepressant trials lasting 6 weeks. RESULTS: The percentage of abrupt improvements that occurred in the first 2 weeks was higher than that for gradual improvements. Abrupt improvements during the first 2 weeks of drug treatment were also less persistent than gradual improvements with drug and no more persistent than improvements with placebo during the same period. However, in weeks 3, 4, and 5, abrupt and gradual improvements with drug were equally persistent and both were more persistent than abrupt improvements with placebo. CONCLUSIONS: These data support the authors' findings about placebo. Abrupt improvements during treatment with both drug and placebo are more likely during the first 2 weeks of treatment and are less likely to persist than gradual improvements. The fact that persistence of abrupt improvements with drug in weeks 1 and 2 appears different from that of gradual improvements but appears no different after week 3 suggests that the mechanism of action of abrupt improvement with drug changes after week 2.

Effects of pill-giving on maintenance of placebo response in patients with chronic mild depression.

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.

Atypical depression, panic attacks, and response to imipramine and phenelzine. A replication.

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.

Cerebral laterality and depression: relations of perceptual asymmetry to outcome of treatment with tricyclic antidepressants.

The relationship of cerebral laterality to outcome of treatment with antidepressants was examined by comparing perceptual asymmetry in subgroups of depressed patients formed on the basis of clinical response to a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI). Perceptual asymmetries of 63 unmedicated depressed patients were assessed for verbal and nonverbal tasks, using dichotic listening and visual half-field methods, and retests were obtained on 49 patients after about 6 weeks of treatment. There were significant differences between TCA responders and TCA nonresponders in dichotic listening and visual field asymmetries. Differences in perceptual asymmetry were specific to TCAs, in that no comparable differences existed between MAOI responders and MAOI nonresponders. Although perceptual accuracy improved following successful TCA treatment, abnormal perceptual asymmetries in TCA responders were present before and after treatment and may thereby represent state-independent characteristics.

Phenelzine and imipramine in mood reactive depressives. Further delineation of the syndrome of atypical depression.

Sixty patients who met Research Diagnostic Criteria for major, intermittent, or minor depressive disorder and had reactive mood without atypical symptoms were treated with imipramine hydrochloride, phenelzine sulfate, or a placebo. These patients, referred to as simple mood reactive depressives, were contrasted with previously published data from 180 atypical depressives. Atypical depressives had the presence of at least one vegetative atypical sign (hypersomnia, hyperphagia, leaden feeling, or rejection sensitivity) but were otherwise indistinguishable from simple mood reactive depressives. In contrast to the atypical depressives for whom phenelzine was effective and imipramine was relatively ineffective, both medications were equivalently good in simple mood reactive depressives. Since all groups did poorly when given a placebo and well when given phenelzine, the salient feature of atypical symptoms may be that they predict poor response to imipramine. Since the difference between imipramine and placebo depends on the diagnostic group, pharmacologic dissection suggests that atypical symptoms in patients with nonautonomous mood may delineate a qualitatively distinct subgroup.

Phenelzine, imipramine, and placebo in borderline patients meeting criteria for atypical depression.

In planning psychopharmacologic treatment of patients with borderline personality disorder (BPD), three partially validated subtypes should be considered. The validity of the schizotypal subtype is supported by their favorable response to neuroleptics as well as by familial and genetic studies. The validity of emotionally unstable character disorder (EUCD) is supported by the presence of neurological soft signs, their negative response to antidepressants, and their positive response to chlorpromazine and lithium. The data presented in this paper suggest that some patients who meet borderline criteria and have atypical depression (patients meeting DSM-III-R criteria for major depression or dysthymia who have reactive mood and any atypical symptoms) clearly benefit from treatment with antidepressant medication. Although some patients with atypical depression who meet borderline criteria will improve with tricyclic therapy, a significantly greater proportion will improve with the monoamine oxidase inhibitor (MAOI), phenelzine.

Social functioning in chronic depression: effect of 6 weeks of antidepressant treatment.

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.

Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders.

Sixty patients with probable atypical depression--defined as meeting Research Diagnostic Criteria for depressive illness, having reactive mood, and having one of four associated symptoms (hyperphagia, hypersomnolence, leaden feeling, and sensitivity to rejection)--took part in a study contrasting phenelzine, imipramine, and placebo. Phenelzine was found to be superior to imipramine and placebo. These results were compared to results from a sample of 120 patients with identical characteristics, except that they had more than one associated atypical symptom (full atypical syndrome). The size of the drug effect was comparable in patients with full atypical and partial atypical syndromes.