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.

Gepirone treatment of atypical depression: preliminary evidence of serotonergic involvement.

This is a report of a controlled trial of gepirone, a 5-hydroxytryptamine (5-HT1A) partial agonist azapirone related to buspirone, in the treatment of atypical depression. The azapirones are of particular interest because their highly selective actions on the serotonergic system may possibly make them useful pharmacologic probes and potentially selective therapeutic agents. Sixty outpatients meeting Columbia criteria for definite or probable atypical depression were enrolled in a double-blind, randomized, placebo-controlled, 8-week clinical trial at a single site. The dosage schedule was fixed flexible, with 10-mg capsules given on a thrice-daily schedule, with doses of up to 120 mg daily. The response rate at 8 weeks for the intention-to-treat sample analyzed with the last observation carried forward was 62% (18 of 29 patients) for gepirone and 20% (6 of 30 patients) for placebo (chi 2 = 9.1; df = 1; p < 0.001). Robust and consistent drug-placebo differences are seen across virtually all rating scales post-treatment. The effect of gepirone was consistent across the levels of concomitant variables, including duration of episode and presence of dysthymia or panic. Gepirone is a novel antidepressant that holds promise for the treatment of atypical depression and that may be of heuristic value because of its relatively specific actions on the serotonergic system.

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.

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.

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.

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.

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.

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.

Dopaminergic sensitivity and cocaine abuse: response to apomorphine.

Ten male patients with chronic cocaine abuse received a single dose of the dopamine agonist apomorphine. Self-ratings of cocaine craving, depression, and anxiety decreased in response to apomorphine. Neuroendocrine response was consistent with central dopaminergic stimulation. Patients in the "craving" phase of the cocaine abuse cycle differed in behavioral but not neuroendocrine response to apomorphine from patients in the "crash" phase. Decrease in cocaine craving correlated with decrease in plasma homovanillic acid (pHVA). Total cocaine consumption correlated negatively with baseline prolactin and pHVA levels and inversely with peak change in prolactin following apomorphine. Patients had blunted neuroendocrine response to apomorphine in comparison to historical normal controls. Implications for the "dopamine" hypothesis of cocaine abuse are discussed.

Lithium treatment for cocaine abusers with bipolar spectrum disorders.

An open trial of lithium carbonate showed little efficacy for 10 cocaine abusers with bipolar spectrum disorders. It may be that the bipolar subgroup of cocaine abusers is heterogeneous and that only a fraction are lithium responsive.

Cholinergic REM sleep induction in atypical depression.

The arecoline REM induction test, a measurement of central cholinergic sensitivity, was performed in 10 patients with atypical depression. Arecoline induced REM sleep significantly more rapidly than placebo. Atypical depressives without evidence of anxiety, in particular those without panic attacks, had a more rapid REM induction response to arecoline than atypicals with anxiety symptoms. We compared our atypical depressives with normal controls and affectively ill patients studied in other laboratories. The rapid REM induction response observed in atypical depressives without anxiety was comparable to that seen in endogenous depressives and euthymic bipolars. Previous studies have demonstrated the presence of cholinergic supersensitivity in the latter two groups of patients. Our results suggest that atypical depressives may be distinguished in their response to arecoline based on their anxiety history, and that cholinergic supersensitivity is present in atypical depressives without anxiety. Additional studies with larger samples and simultaneously studied control groups are necessary to test these preliminary findings.

Relevance of DMS-III depressive subtype and chronicity of antidepressant efficacy in atypical depression. Differential response to phenelzine, imipramine, and placebo.

One hundred ninety-four nonmelancholic depressed outpatients with features of atypical depression took part in a 6-week randomized trial of imipramine hydrochloride, phenelzine sulfate, and placebo. Their courses of illness were also rated for chronicity. Significantly more patients responded to phenelzine (71%) than to imipramine (48%), which benefited significantly more patients than placebo (26%). Both chronicity and DMS-III diagnosis predicted response on several outcome measures. For example, patients with dysthymic disorder responded better to treatment than did those with major depression, suggesting that dysthymic disorder can be treated with medication. Placebo response correlated inversely with chronicity, regardless of DMS-III diagnosis. Atypical depression and longitudinal course of illness may add to the usefulness of DMS-III depressive diagnosis as a predictor of antidepressant response.

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.

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.

Phenelzine treatment of melancholia.

Monoamine oxidase (MAO) inhibitor antidepressants are widely thought by clinicians and researchers to be ineffective in the treatment of endogenous depression. This study reports an open clinical trial in which seven of eight outpatients (88%) with melancholia responded to phenelzine treatment. This response rate is comparable to the response to tranylcypromine in a previous study at our clinic. These results suggest that MAO inhibitors are effective for outpatients with endogenous depressive syndromes. The use of MAO inhibitors may be an alternative treatment for patients who cannot tolerate or who have not responded to tricyclic antidepressants.