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Previous research suggests that 16% to 50% of individuals with schizophrenia abuse cocaine (1–3). The prevalence of cocaine abuse in persons with schizophrenia is problematic, considering the debilitating effect that the drug can have on acute symptoms and on illness course. Individuals with schizophrenia and cocaine dependence display more positive symptoms, fewer negative symptoms, and higher rates of extrapyramidal symptoms (EPS) (4,5), which may result from an interaction between dopamine and the psychostimulant properties of cocaine (6). It is widely accepted that aberrations in the dopamine system play a role in the etiology of schizophrenia (7,8) and the maintenance of cocaine addiction via craving (9–11). To examine the clinical impact of these dopamine abnormalities, we compared self-report craving among cocaine addicts and cocaine addicts with schizophrenia. Individuals with schizophrenia and cocaine dependence had significantly more craving, which remained stable over a 72-hour period (12). In a follow-up study, we included a cue-exposure paradigm and found that 97% of the cocaine-dependent persons with schizophrenia were cue-reactive, suggesting the need to target this state in treatment (11). Owing to the rapid increase in dopamine following cocaine use, which can persist for weeks and result in increased craving and depression, researchers have examined dopamine antagonists for treatment of protracted withdrawal. They found haloperidol and fluphenthixole reduced craving and relapses in both schizophrenia and nonschizophrenia cocaine-dependent patients (13–15). In addition, researchers have begun studying atypical antipsychotics for the treatment of cocaine addiction alone and schizophrenia and cocaine dependence concurrently. This class of medication has the advantage of offering a lower side-effect profile and of regulating the central serotonergic system, which plays a role in cocaine craving (16). Preliminary data suggest that clozapine (17,18) and olanzapine (19) have been efficacious in reducing craving and preventing substance-abuse relapses among dually diagnosed individuals. Risperidone has also shown some efficacy in reducing craving in nonschizophrenia cocaine addicts (20,21). Therefore, we were interested in conducting a preliminary, open-label, 6-week study to determine whether risperidone is more efficacious than are typical neuroleptics for reducing cue-elicited craving, improving symptoms, and preventing relapses during protracted withdrawal in individuals dually diagnosed with schizophrenia and cocaine dependence. MethodsWe recruited 18 cocaine-dependent schizophrenia patients from the Veterans Administration, New Jersey Health Care System’s mentally ill, chemical-abuse program for the open-label, 6-week trial. Although the investigator was not blind to medication condition, the individual conducting the cue-elicited craving and schizophrenia-symptom evaluations was blind to medication status. Subjects were not blind to medication type but were not made aware of anticipated results of the study and were instructed not to discuss their prescription with the research assistant. For inclusion in the study, subjects met the following criteria: 1) they presented with a DSM-IV diagnosis for cocaine dependence and schizophrenia, which a psychiatrist and the first author made independently, 2) they reported using at least 6 grams of cocaine monthly, and 3) they responded to cue exposure with increased craving. Subjects were excluded if they met DSM-IV criteria for an additional Axis I disorder other than schizophrenia and cocaine dependence; had a history of alcohol, opiate, barbiturate, benzodiazapine, or marijuana dependence; were taking other prescribed medication that could affect the central nervous system (CNS); had a history of seizures; were pregnant women; or had an evidenced chronic disease of the CNS other than schizophrenia. Because nicotine addiction is present in more than 70% of persons with schizophrenia (22), smokers were not excluded in this study. After giving informed consent, subjects underwent the cue-exposure procedure. During cue exposure, subjects were seated in our laboratory and were shown videotapes of people smoking cocaine and of people administering intravenous cocaine. Previous research shows that these cues elicit cocaine craving (10,11). To measure baseline craving, subjects completed the Voris Cocaine Craving Questionnaire (VCCQ), a 4-item, self-report, 50-point visual analogue scale with good reliability and validity (10,23). The scale items focus on changes in craving intensity, happy or depressed mood, increased or decreased energy, and physical health and feeling sick. After viewing the videotape cues, the subjects were asked to complete the VCCQ again. The subjects also completed a baseline cocaine demographic survey and the Positive and Negative Syndrome Scale (PANSS) (24). The VCCQ with the cue exposure procedure and the PANSS were conducted weekly throughout the study. Cocaine abstinence was ascertained by self-report and was substantiated with random urine toxicology screens. A total of 18 subjects were initially recruited on typical neuroleptics, and the patients assigned to the atypical group (n = 8) were cross-tapered to risperidone. The risperidone dosage was once daily with a 2, 4, and 6 mg titration schedule on days 1, 2, and 3, and a maximum dosage of 6 mg daily. In some cases, titration was slower with increments of 1 mg daily, also to a maximum dosage of 6 mg daily. The typical neuroleptic medications received in the comparison group included haloperidol, fluphenazine, and chlorpromazine. At the discretion of the study physician, subjects in both groups could receive anticholonergic medication. We conducted a last-observation-carried-forward (endpoint) analysis of the data. Under this procedure, only subjects who received cue-elicited craving and PANSS symptom ratings after 2 weeks of medication treatment were considered in the analysis. Student’s t-tests were conducted to measure group differences in cocaine craving. A Fisher’s Exact test was used to examine differences in relapse and treatment compliance. ResultsCharacteristics of the patients in the 2 groups were similar (Table 1). A total of 9 patients, 6 in the risperidone group and 3 in the typical antipsychotic group, completed the 6-week study. No ratings data were available for 2 patients: at week 3, 1 discontinued the trial; at week 4, 3 discontinued; and at week 5, 3 discontinued. Patients in the 2 groups received equivalent medication dosages (chlorpromazine [CPZ] equivalents). The mean daily CPZ typical antipsychotic dosage was 522.9 mg, SD 200.4, while the mean dosage of risperidone was 550.0 mg, SD 141.4; t = 0.306, P = 0.764. However, the risperidone-treated group (n = 8) had a greater number of cocaine-use days during the month prior to entering the study, compared with the typical neuroleptic group (n = 10) (mean 11.8, SD 8.7 vs mean 5.3, SD 5.9; t = 1.8, P = 0.093). According to the endpoint analysis, the risperidone-treated subjects
statistically had significantly less cue reactivity on the intensity
(mean 7.88, SD 7.1 vs mean 25.63, SD 13.5; t = 3.3, P
= 0.005) and depression (mean 39.0, SD 7.7 vs mean 26.0, SD 13.3;
Further, upon study completion, 12.5% of the patients who received risperidone (n = 1) relapsed compared with 70% of the patients on typical neuroleptics (n = 7) (Fisher’s Exact Test P = 0.025). A relapse was defined as any substance abuse, and in the data analysis, patients with multiple relapses were only counted once. Although not significant, 25% of the risperidone-treated individuals (n = 2) dropped out of the study, compared with 70% of the individuals receiving a typical neuroleptic (n = 7) (Fisher’s Exact Test P = 0.153).
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