The management of treatment resistance in depressed patients with substance use disorders.

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.