Imipramine treatment of alcoholics with primary depression: A placebo-controlled clinical trial.

BACKGROUND: Depressive disorders are commonly comorbid with alcoholism, particularly in treatment-seeking samples. If antidepressant treatment were safe and improved the treatment outcome in the subset of actively drinking alcoholics with depression, this would be of clinical importance. METHODS: We conducted a randomized, 12-week placebo-controlled trial of imipramine hydrochloride combined with weekly relapse prevention psychotherapy. The subjects were 69 actively drinking alcoholic outpatients with current depressive disorders. The first onset of depression was either antecedent to the abuse of alcohol or occurred during prolonged periods of sobriety. Depression and drinking outcomes at 12 weeks, as well as their relationship, were measured. RESULTS: Imipramine treatment was safe and associated with improvement in depression in both adequately treated and intention-to-treat samples. While there was no overall effect on drinking outcome, patients whose mood improved showed decreased alcohol consumption that was more marked in those treated with imipramine. CONCLUSIONS: Imipramine treatment is effective for primary depression among actively drinking alcoholic outpatients, and may improve alcoholic outcome for those whose depression responds to treatment.

Imipramine treatment of opiate-dependent patients with depressive disorders. A placebo-controlled trial.

BACKGROUND: The literature is inconclusive on the role of antidepressant medications in treating drug dependence. Studies have either not focused on depressed patients or have selected patients with depressive disorders based on cross-sectional symptoms rather than a syndromal diagnosis. A clinical trial of an antidepressant was, therefore, conducted on drug-dependent patients with syndromal depression. METHODS: Patients receiving methadone hydrochloride maintenance treatment were selected if they met the criteria for a DSM-III-R depressive disorder that was chronologically primary, had persisted during a past abstinent period or was long-standing, and persisted during at least 1 month of stable methadone treatment. Subjects were randomized to a 12-week, double-blind, placebo-controlled trial of imipramine hydrochloride. A favorable response was defined as a Clinical Global Impression scale score for depression of 2 ("much improved") or 1 ("very much improved") and at least a 75% reduction in self-reported drug or alcohol use or abstinence. RESULTS: One hundred thirty-seven patients were randomized, and 84 completed a minimum adequate trial of at least 6 weeks. Among the 84 adequately treated patients, 57% (24/42) receiving imipramine were rated as responders compared with 7% (3/42) receiving placebo (P < .001). On measures of mood, there was a robust effect of imipramine. Imipramine was superior to placebo on some self-reported measures of substance use and craving, and mood improvement was associated with improvement in self-reported substance use. However, few patients achieved urine-confirmed abstinence. CONCLUSIONS: Imipramine was an effective antidepressant in patients receiving methadone who were selected via syndromal criteria for depressive illness. Imipramine may reduce substance abuse among patients whose mood improves; however, this effect was less robust.

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.

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.

Chronological milestones to guide drug change. When should clinicians switch antidepressants?

BACKGROUND: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. METHODS: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. RESULTS: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received placebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. CONCLUSIONS: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression.

OBJECTIVE: Data from controlled studies concerning the response rates of patients to a second antidepressant medication after they have been unresponsive to a systematic trial of another antidepressant are extremely useful to clinicians for rational prescription of pharmacotherapy. Such information allows making an accurate prognosis, sustaining realistic hope in the patient, and achieving the best possible therapeutic outcome. This study was designed to add to the scanty literature available on this subject. METHOD: Eighty-nine mood-reactive, nonmelancholic, mainly chronically depressed outpatients at a university research clinic who were unresponsive to vigorous double-blind trials of imipramine or phenelzine were crossed over to treatment with the other drug under double-blind conditions. RESULTS: Of 46 patients previously unresponsive to imipramine who completed phenelzine treatment, 31 (67%) responded to phenelzine. Of 22 patients previously unresponsive to phenelzine who completed imipramine treatment, nine (41%) responded to imipramine. The difference in response rates was statistically significant. Even after they had shown no response to 7 weeks of placebo and 6 weeks of imipramine treatment, 10 (83%) of 12 patients who then completed treatment with phenelzine responded. CONCLUSIONS: These data suggest that among chronically ill, mood-reactive depressed patients with many symptoms of atypical depression, phenelzine is strikingly effective in those who have been nonresponders to imipramine and should be tried in such patients.

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.

Imipramine treatment of cocaine abuse: possible boundaries of efficacy.

A 12-week placebo-controlled, randomized clinical trial was undertaken to evaluate imipramine as a treatment for cocaine abuse, and to examine whether its effect may be limited to subgroups defined by route of use or by diagnosis of depression. One-hundred thirteen patients were randomized, stratified by route of use and depression. All patients received weekly individual counseling. Compared to placebo the imipramine group showed greater reductions in cocaine craving, cocaine euphoria, and depression, but the effect of imipramine on cocaine use was less clear. A favorable response, defined as at least 3 consecutive, urine-confirmed, cocaine-free weeks was achieved by 19% (11/59) of patients on imipramine compared to 7% (4/54) on placebo (P < 0.09). The imipramine effect was greater among nasal users--33% (9/27) response on imipramine vs. 5% (1/22) on placebo (P < 0.02). Response was also more frequent, but not significantly so, among depressed users on imipramine (26%, 10/38) than on placebo (13%, 4/31) (P < 0.19). Response rates were low in intravenous and freebase users and those without depression. Considered together with the literature on desipramine, these data suggest tricyclic antidepressants are not promising as a mainstay of treatment for unselected cocaine abusers. However, tricyclics may be useful for selected cocaine abusers with comorbid depression or intranasal use, or in conjunction with a more potent psychosocial intervention.

The efficacy of imipramine and psychotherapy in early-onset chronic depression: a reanalysis of the National Institute of Mental health Treatment of Depression Collaborative Research Program.

The authors compared the effectiveness of Cognitive Behavioral Therapy (CBT), Interpersonal Psychotherapy (IPT), Imipramine Clinical Management (ICM) to Placebo Clinical Management (PCM) for outpatients with early-onset chronic depression (N = 65) in the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (TDRP). The post-treatment depression scores of the CBT. IPT, and ICM groups were not significantly different from the PCM group. We did not find a relationship between the duration of Major Depression and response to a specific treatment. Studies are needed to determine if combining psychotherapy with medication improves social functioning and enhances the quality of life for patients with chronic 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.

Modern psychometric methods for detection of differential item functioning: application to cognitive assessment measures.

Cognitive screening tests and items have been found to perform differently across groups that differ in terms of education, ethnicity and race. Despite the profound implications that such bias holds for studies in the epidemiology of dementia, little research has been conducted in this area. Using the methods of modern psychometric theory (in addition to those of classical test theory), we examined the performance of the Attention subscale of the Mattis Dementia Rating Scale. Several item response theory models, including the two- and three-parameter dichotomous response logistic model, as well as a polytomous response model were compared. (Log-likelihood ratio tests showed that the three-parameter model was not an improvement over the two-parameter model.) Data were collected as part of the ten-study National Institute on Aging Collaborative investigation of special dementia care in institutional settings. The subscale KR-20 estimate for this sample was 0.92. IRT model-based reliability estimates, provided at several points along the latent attribute, ranged from 0.65 to 0.97; the measure was least precise at the less disabled tail of the distribution. Most items performed in similar fashion across education groups; the item characteristic curves were almost identical, indicating little or no differential item functioning (DIF). However, four items were problematic. One item (digit span backwards) demonstrated a large error term in the confirmatory factor analysis; item-fit chi-square statistics developed using BIMAIN confirm this result for the IRT models. Further, the discrimination parameter for that item was low for all education subgroups. Generally, persons with the highest education had a greater probability of passing the item for most levels of theta. Model-based tests of DIF using MULTILOG identified three other items with significant, albeit small, DIF. One item, for example, showed non-uniform DIF in that at the impaired tail of the latent distribution, persons with higher education had a higher probability of correctly responding to the item than did lower education groups, but at less impaired levels, they had a lower probability of a correct response than did lower education groups. Another method of detection identified this item as having DIF (unsigned area statistic=3.05, p<0.01, and 2.96, p<0.01). On average, across the entire score range, the lower education group's probability of answering the item correctly was 0.11 higher than the higher education group's probability. A cross-validation with larger subgroups confirmed the overall result of little DIF for this measure. The methods used for detecting differential item functioning (which may, in turn, be indicative of bias) were applied to a neuropsychological subtest. These methods have been used previously to examine bias in screening measures across education and ethnic and racial subgroups. In addition to the important epidemiological applications of ensuring that screening measures and neuropsychological tests used in diagnoses are free of bias so that more culture-fair classifications will result, these methods are also useful for the examination of site differences in large multi-site clinical trials. It is recommended that these methods receive wider attention in the medical statistical literature.

How symptomatic do depressed patients remain after benefiting from medication treatment?

Symptom Check List-90 (SCL-90) scores of 318 moderately depressed, nonmelancholic outpatients treated with phenelzine, imipramine, or placebo were compared with scores obtained from a demographically matched control group of 69 "normal" subjects. Pretreatment scores of depressed patients were significantly higher than those of the control group; after 6 weeks of treatment, they were indistinguishable from scores of the control group. These results suggest that symptoms of moderately depressed patients who benefit from treatment not only decrease from baseline, but are reduced to a level of symptomatology that is psychiatrically normal.

General versus systematic inquiry about emergent clinical events with SAFTEE: implications for clinical research.

This study compares two methods for elicitation of treatment-emergent side effects. One is the open-ended general inquiry and the other is a specific inquiry that asks about a wide range of events thought to be treatment-related. The study goal was to determine the extent to which the specific inquiry method elicits clinically useful information over and above that elicited by the general inquiry method. The assessment instrument we used is SAFTEE, a structured interview schedule developed by the National Institute of Mental Health. We looked for differences between general and specific inquiry formats in terms of number of events elicited, type of event, severity, functional impairment, and clinician action taken. We found that both methods contributed to elicitation of events that, in the clinician's opinion, required some change in management. However, events reported on the General Inquiry form were significantly more distressing, more often interfered with daily functioning, and elicited more extensive changes in clinical management. No medically serious events were elicited on the specific inquiry form alone. Based on these findings, and in view of the amount of time and effort required to administer and score it, we do not recommend the specific inquiry form of SAFTEE as a standard assessment tool for routine use in all clinical trials. We do consider it to be a useful method for comprehensive elicitation about treatment-emergent effects in targeted and specific research contexts. We see the schedule as a comprehensive document or library of queries to be tailored to the needs of individual protocols.

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.

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.

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.

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.

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.