The Epidemiologic Catchment Area study1 revealed that 76.1% of individuals with diagnoses of cocaine abuse or dependence have a lifetime history of a psychiatric illness. While individuals with cocaine dependence are difficult to engage and retain in treatment,2,3 the presence of a comorbid psychiatric illness results in an especially poor course and treatment response.4 Data are limited on the use of antipsychotics in such "dual diagnosis" patients. While conventional antipsychotics are safe and effective, their side-effect profile is disconcerting and may contribute to the drive to misuse substances.5,6 On the other hand, clozapine7,8 and olanzapine9 have been reported to decrease both cocaine use and psychiatric symptoms in patients with comorbid psychotic disorders. Quetiapine, another antipsychotic, has been reported to decrease depression and mania symptoms as well as cocaine craving in bipolar patients with cocaine dependence.10
Risperidone, a 5-hydroxytryptamine-2a (5-HT2a) and dopamine (DA) D2 antagonist, is an atypical antipsychotic medication that has received some attention in the field of substance addiction. Animal studies suggest that risperidone blocks cocaine-induced enhancement of DA release and decreases cocaine self-administration.11,12 Conflicting findings have been reported among patients with cocaine-dependence without comorbid psychiatric illnesses. For example, De La Garza et al.13 and Roy et al.14 found that risperidone reduced cocaine craving, whereas Grabowski et al.15 reported no significant reduction in cocaine use in a double-blind, placebo-controlled trial with cocaine dependent patients without comorbid psychiatric illness. Smelson et al.16 found no difference in cocaine craving in patients without psychiatric illness who were treated with risperidone versus those who received placebo who underwent a cue-exposure procedure.
However, support for use of risperidone in dual diagnosis patients has been accumulating.17-20 Risperidone has been used safely and effectively in patients with various psychiatric illnesses and comorbid substance use disorders.21 In this report, we describe our experience using risperidone to treat psychiatric disorders in cocaine-dependent patients.
Patients and Program
During a 3-year period, approximately 300 patients admitted to a 180-bed, voluntary, post-detoxification, intermediate-care, free-standing residential substance abuse program for men were referred to one of the authors (MJA) for psychiatric assessment. The facility is unlocked, and patients earn graded increases in privileges, both on- and off-grounds, as they progress through the program. Funded by the Commonwealth of Massachusetts Department of Public Health, the program provides individual counseling, as well as a full range of group treatments, including self-help groups (e.g., Alcoholics Anonymous), group therapy, occupational therapy, and vocational rehabilitation. Twenty-two patients, all of whom underwent inpatient detoxification prior to admission to this program, were diagnosed with cocaine dependence and comorbid psychiatric disorders. Of these 22 patients, 6 (27%) dropped out after the initial assessment prior to a second meeting with the research physician, with no subsequent follow-up interviews. The average risperidone dosage in these 6 patients was 1.18 mg/day. The remaining 16 patients are the focus of this article. All patients were male. This was a retrospective chart review, for which IRB review was waived.
Information on demographics, psychiatric diagnoses, other substance use, and concomitant medications is summarized in Table 1. One clinician (MJA) used the Structured Clinical Interview for DSM-III-R (SCID)22 to assign diagnoses. All patients had at least one other substance use diagnosis in addition to cocaine dependence. Of the 16 patients, 13 were taking psychiatric medications at the time of the assessment. All 16 patients were treated with risperidone, with a mean starting dose of 2.3 mg/day, and were assessed weekly while they remained in the program. The mean daily dosage of risperidone at the time of discharge from the program was 3.41 mg.
Assessments were made by one clinician (MJA) using the Clinical Global Impressions scale23 to assess overall functioning and a Likert scale for craving. The emergence of side effects was also noted during clinical interviews and using the Abnormal Involuntary Movement Scale.24 The patients were also asked about cocaine use. Likewise, individual counselors, who were blinded to the patients' medication regimens, were asked weekly about patient status and their suspicions about cocaine use. When clinically indicated, complete blood counts and liver function tests were also obtained. The average length of follow-up-the number of days between the first and last meetings with the psychiatrist-was 32.6 days. For the 13 patients whose exact date of abstinence was known, the mean time abstinent at the time of the initial evaluation by the psychiatrist was calculated to be 44.3 days. This represents the average amount of time between last use of any substance and starting on risperidone.
Table 2 summarizes the results. Of the 16 patients, 13 (81%) were rated as improved or much improved on the CGI. The same patients reported subjective improvement and were rated as improved or much improved by the substance abuse counselors. At baseline, all patients reported moderate to severe cocaine craving, whereas at their final follow-up visits, all 16 patients reported mild or no craving and no cocaine use. Neither psychiatric symptoms nor craving worsened for any patient. When the counselors had concerns that any patients in the treatment program were using substances, all patients in the program at the time received urine drug screening. Four patients in this study were involved in such across-the-board screening, one of whom tested positive for heroin and was discharged. None of the 16 patients in the study was discharged for cocaine use. Of note, the rate of early discharge for the rest of the treatment population during this time period was 19%, with most of these discharges due to alcohol or drug use, compared with 6% (1/16) for the study population. Of the 16 patients in this study, 14 (88%) completed the program and 9 (56%) were discharged to the next level of care. The two patients who were discharged early were treated for 44 and 26 days, respectively.
Of the 16 patients, 13 (81%) were taking another psychiatric medication, with 10 patients receiving antidepressants and 5 mood stabilizers. No patient developed extrapyramidal side effects or hypomania. One patient, who was also receiving benztropine and haloperidol, reported sedation and dizziness. Complete blood counts (CBCs) and liver function tests (LFTs) were completed in 6 patients because of medical history. CBC results were all within normal limits. In 3 patients, LFTs, specifically alanine aminotransferase and aspartate aminotransferase, were elevated at baseline, but remained stable during the course of treatment.
The results of this naturalistic, open trial suggest that risperidone is both safe and well-tolerated, even when combined with other medications, in cocaine-dependent patients with comorbid psychiatric illness. This report also suggests that risperidone may decrease cocaine craving and use. Of note, risperidone treatment was effective despite a high level of clinical pathology, as evidenced by the high rate of substance use and psychiatric comorbidity.
While the 33-day follow-up period is not long by clinical trial standards, it is substantial for this population of patients with notoriously difficult-to-treat illnesses and poor treatment adherence.25-27 Furthermore, in comparison to the program's annual completion rate of 32% (ranging between 21% and 41% per month during a recent 1-year period), in this trial 14 patients (88%) completed the program, and 9 (56%) moved on to the next level of care. Interestingly, a comparison of the mean risperidone dosage between the 16 who participated (mean dose = 3.41 mg/day) and the 6 patients who dropped out (mean dose = 1.18 mg/day) shows a remarkable disparity. Due to our small sample size, we were not able to conduct a statistical analysis. However, the difference may suggest risperidone's role in treatment retention and its ability to assist patients in participating in and completing substance abuse treatment.
The lack of adverse events, involuntary movements, and side effects is notable, especially given both the sensitivity to side effects and the high prevalence of medical disorders in the cocaine-dependent population.4,28 The relatively low dose of risperidone may account for these findings. The fact that no patient developed hypomania is significant, since that state can predispose to substance abuse relapse. Also, the minimal need for anticholinergic medication is important because such medications have abuse potential. In fact, 3 patients referred to the program were taking an anticholinergic medication and 2 of these were also taking a conventional antipsychotic. In both cases, the antipsychotic and the anticholinergic were tapered off after the initiation of risperidone treatment. Furthermore, the clinical improvement demonstrated in this study does not appear to have been a result only of abstinence, since, in the 13 cases for which a confirmed sobriety date was known, the average number of days of abstinence from all substances, not just cocaine, before beginning risperidone treatment was 44.3 days.
This study had a number of limitations, including a small sample size and naturalistic design. All patients participated in an intensive, comprehensive substance abuse psychosocial rehabilitation program. While we cannot determine how much the psychosocial interventions contributed to the positive results, accumulating evidence has demonstrated that psychosocial interventions significantly enhance outcomes of pharmacological treatments for substance abuse.29 Also, almost all patients were receiving at least one other psychiatric medication. While the use of concomitant medications could be considered a confounding factor, at the same time, the use of risperidone in combination with other psychiatric medications in this study also demonstrated that risperidone is safe and well tolerated by psychiatric patients with cocaine dependence, as evidenced by minimal side effects and no adverse events. Additionally, this naturalistic study was conducted in an inpatient setting, with an all-male, virtually all-Caucasian, population and, thus, is not generalizable to the general psychiatric population with cocaine dependence. For example, the reduction seen on the cocaine craving measure could be due to patients residing in a controlled setting and might not be observed in an outpatient setting. Finally, data on substance use while in treatment are based solely on patient report. At this program, toxic screens are not conducted routinely but only when clinical suspicion of use exists. Interestingly, the clinical staff, all of whom were blinded to medication regimen, had no such suspicions about this cohort. Furthermore, some studies have shown that, in the absence of suspicion of use, clinical interview is as good or better than a urine toxicology screen in identifying substance use in dual diagnosis populations.30,31
Despite its limitations, this study suggests that risperidone is safe and effective for psychiatric disorders and may be helpful in reducing craving and cocaine use in cocaine-dependent patients with a comorbid psychiatric illness. These findings warrant further investigation with double-blind, placebo-controlled clinical trials to examine the effectiveness of atypical antipsychotic agents for cocaine-dependent patients with comorbid psychiatric illnesses.
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