Faculty Bibliography

This chapter reviewed the controlled tricyclic trials for cocaine abuse with both a clinician's and a researcher's eye in order to develop methodologic recommendations for future medications development efforts. The review is summarized in table 2. The main points are that attrition is high, particularly early in the trials; placebo effects are high, particularly early and in subjective or self-report measures; and the samples may be heterogeneous with responsive (depressed, mild severity) and unresponsive (antisocial personality) subgroups. Methodologic recommendations are summarized in table 3. Emphasis is placed upon the potential heterogeneity of cocaine abusers and targeting treatments to subgroups on the one hand, and various methodologic recommendations to tighten up the design of early, small-scale pilot trials on the other. These include use of potent, standardized interventions to reduce attrition; a prolonged, single-blind placebo lead-in to wash out early dropouts and placebo effects; discarding the uncontrolled pilot trial in favor of crossover, discontinuation, or multiple-baselines designs; and considering the impressions of experienced clinicians as well as objective, urine-based measures when judging efficacy. These recommendations are all arguable in that they have disadvantages as well as advantages and that they all depart to some extent from current practice and wisdom. It is hoped that they will promote discussion and stimulate methodologic innovation in the search for effective medications for cocaine abuse.

The dropout rates among cocaine abusers in outpatient treatment programs have averaged 55%. We sought to find patient predictor variables associated with early attrition. Dropouts were more likely to be African-American or Hispanic-American, younger, with an earlier onset of substance abuse. Among minorities, those with more education were less likely to drop out. Patients who were less educated and smoked or injected cocaine were particularly prone to discontinue treatment prematurely. The implications of these findings, and promising interventions for reducing the dropout problem, are discussed.

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.

General principles for treatment-resistant psychiatric disorders include reevaluation of diagnosis, search for hidden comorbidity, and systematic trials of alternative treatments and treatment combinations. For the combination of refractory depression and substance abuse, alternative approaches to both problems need to be tried, as suggested in the decision tree in Figure 1. Recognition of a previously unappreciated substance abuse problem or institution of more effective substance abuse treatment (see Table 2) can improve the outcome of depression. Hospitalization is often useful to enforce abstinence and to clarify the diagnosis of depression, and is particularly indicated if substance abuse is severe. If hospitalization is not possible then features of the history, such as relative onsets of depression and substance abuse, can be considered to support the diagnosis. TCAs and SSRIs have been studied in depressed substance abusers and should be the first lines of treatment. If these fail, other medications, medication combinations, or ECT should be considered, extrapolating from the general literature on treatment of refractory depression. In general, single agents should be preferred to combinations, as this reduces the odds of drug-drug interactions in patients who may abuse a variety of substances. Impairment by antidepressant agents of hepatic metabolism of other drugs should be considered, and sertraline, for example, might be preferred over fluoxetine for this reason. For each case, the known side effects and risks of a given antidepressant medication must be considered in the context of a patient's substance abuse pattern and medical problems. Such risk:benefit analyses are often difficult, as illustrated in the cases presented. Finally, although it is a rare occurrence, antidepressant medications that are anticholinergic or amphetamine-like may be abused, and this needs to be monitored. Alcohol or drug abuse history is a likely risk factor for benzodiazepine abuse, and benzodiazepines should, therefore, be avoided or used with caution. These recommendations for management of treatment-resistant depression with substance abuse are based upon clinical experience and extrapolation from the literature on treatment-resistant depression, treatment of substance abuse, and initial treatment of depression in substance abusers with TCAs and SSRIs. More treatment research is needed, particularly on Type IV patients where both depression and substance use are treatment resistant.