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The Epidemiologic Catchment Area study indicated that the odds of having a substance abuse diagnosis were 4.6 times as high for those with schizophrenia as for the rest of the population (Regier et al., 1990). Several etiological models have been proposed to explain the comorbidity, of which self medication hypothesis is of particular interest (Khantzian, 1985). This model, in a broader sense, interprets substance abuse as the patient's attempt to overcome the distressing effects of the illness and/or those resulting from its treatment. Conventional antipsychotic drugs are known to elicit dysphoric responses in a substantial proportion of schizophrenic patients, and it is possible that these patients learn to relieve or modulate the unpleasant feelings through the use of illicit drugs (Dixon et al., 1991).Neuroleptic dysphoria (ND) is a subtle, underrecognized side effect of conventional (typical) antipsychotic medications that is often described as an unpleasant subjective response, characterized by irritability, tiredness, listlessness, and lack of interest or ambition (Awad, 1993; VanPutten et al., 1984). Reported prevalence rates ranged between 5% to 40% of all schizophrenic patients treated with conventional antipsychotic drugs (Weiden et al., 1989). The occurrence and persistence of these effects have been linked to drug aversiveness, noncompliance with medications, poor symptom control, frequent relapses of the illness, and compromised quality of life (Awad et al., 1995). A hypothesis viewing the occurrence of substance abuse in schizophrenia as a self-medication process, as well as the role of ND as a putative mediating factor, was tested in this preliminary investigation.We hypothesized that the prevalence of substance abuse would be higher among schizophrenic patients who experience ND, and it was tested by studying the association between prevalence of ND and a subsequent development of substance abuse in a sample of schizophrenic patients treated with conventional antipsychotic drugs. Using a retrospective case controlled study design, cohorts of patients with or without the specified risk factor (ND) were identified, the prevalence of a defined disorder (substance abuse) was ascertained, and measures of association were calculated.The survey was conducted in an urban, community-based clinical population, who were participating in the aftercare program of a university-affiliated teaching hospital. A total of 223 patients receiving maintenance antipsychotic drug therapy for schizophrenia (DSM-IV) were included in the study. Individuals with a history of substance abuse predating the onset of schizophrenia and antipsychotic drug therapy, schizo-affective disorder, primary substance abuse disorder, or a concurrent diagnosis of mental retardation were excluded. A sociodemographic profile of the sample indicated a predominantly young adult (age 35.8 ± 9.4 years), white (84%), unmarried (89%), unemployed (91%) population with a slight excess of men (52.9%). Clinical histories revealed an illness duration of 9.2 ± 5.4 years, a mean age of onset of illness as 22.3 years, mean number of hospitalizations as 5.2, and a maintenance antipsychotic dose of 873 ± 432 mg. (chlorpromazine equivalents).Of the total sample of 223 patients, a subsample of 129 patients was noted to have a history of psychiatric hospitalization within the previous 1 year. Patients in this subsample, hereafter referred to as the inpatient (IP) group, were relatively younger (mean age 29.4 years) and had a history of poor compliance with treatment, higher number of repeated short hospitalizations (mean 9.4), and a pattern of not adhering to the treatment program. The remaining 94 patients, hereafter referred to as the outpatient (OP) group, were relatively older in age (mean age 41.2 years), clinically stable, complied with treatment, and had a history of fewer IP admissions.