Steven Wager

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.

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.

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.

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.

Psychopharmacology in Clinical Practice

Psychopharmacology is the study of natural and synthetic substances (i.e., drugs) that affect cognitive and emotional functioning. Clinical psychopharmacology is an extension of this discipline, and involves the treatment of mental disorders with medication. Due to the many advances in clinical psychopharmacology over the past three decades, a number of mental disorders are now treated with some form of medication. In many cases, these pharmacologic treatments are used in conjunction with psychotherapy, and this combination of treatment modalities has grown increasingly common. As a result, the psychologist often is the primary therapist for patients being treated with medication. In outpatient settings, a psychologist may be the sole person responsible for determining whether to refer a patient for treatment with medication. We believe, therefore, that it is important for clinical psychologists to develop some familiarity with psychopharmacologic agents and the indications for their use.

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.