Depression is the most common psychiatric disorder in substance abusers, and results in a poorer prognosis and response to traditional chemical dependence and mental health treatment approaches. This article focuses on the use of pharmacotherapy in the treatment of the cocaine addict with secondary depression and provides general clinical treatment guidelines. It also reports on a study in which depressed, methadone-maintained cocaine addicts were treated in a 12-week placebo-controlled trial that compared two pharmacological agents. Patients were randomly assigned to receive placebo, amantadine (a dopamine agonist) or desipramine (a tricyclic antidepressant). The effects of pharmacotherapy were assessed on program retention, cocaine craving, cocaine usage, and depressed mood. Compared to the placebo-treated patients, it was found that the medication-treated depressed patients had a dramatic decrease in their reported cocaine usage (84% versus 17%) and cocaine craving (48% decrease versus 29% increase). Also, the medication-treated depressed patients dramatically increased the percentage of cocaine-free urines compared to the placebo-treated depressed patients who actually decreased their percentage of cocaine-free urines. A measure of depressive symptoms (Beck Depression Index score) increased 100% for the placebo-treated depressed patients, yet remained stable for the medication-treated depressed patients.