Depressive symptomatology is expressed across a wide spectrum of psychiatric disorders including major depression and schizophrenia. Further, depressive symptomatology is also observed in individuals undergoing withdrawal from chronic exposure to various drugs of abuse including cocaine, amphetamine and nicotine. The negative affective state associated with drug withdrawal is phenomenonologically similar to that observed in depressed and schizophrenia patients suggesting that common underlying pathophysiological deficits may be involved in the depressive symptomatology seen across these different psychiatric disorders. The aim of the present review is to examine clinical and preclinical evidence in support of a common neurobiological substrate mediating the negative affect associated with different psychiatric illnesses. First, clinical and epidemiological data are presented demonstrating the high comorbidity between nicotine and psychostimulant dependence, and depression or schizophrenia. It is hypothesized that drug-use may represent an attempt to self-medicate an underlying negative affective state present in depressed and schizophrenia patients. Second, preclinical findings are presented that demonstrate common neurochemical deficits in drug withdrawal and depression. Taken together, these clinical and preclinical data support the hypothesis that common neurobiological substrates may mediate the depressive state observed across psychiatric diagnostic categories. Therefore, it is proposed that the study of drug-induced depressions in laboratory animals may have heuristic value in identifying the mechanisms underlying the depressive symptomatology associated not only with drug withdrawal but also major depression and schizophrenia.