Schizophrenia and Substance Abuse: Is There a Role for Atypical Antipsychotics?

Clozapine
What is the evidence that the atypical antipsychotics are superior to conventional antipsychotics in treating substance abuse in patients with schizophrenia? The most compelling evidence for the efficacy of the atypicals in treating substance abuse is with clozapine(Drug information on clozapine); this includes data from preclinical studies, case reports, retrospective chart reviews evaluating patients in whom treatment was started with clozapine, and uncontrolled comparison studies. Laboratory animal studies suggest that clozapine affects cocaine preference and administration¹⁵ and blocks psychomotor stimulant behavior induced by cocaine.¹⁶ Case reports have suggested that clozapine decreases cocaine craving¹⁷ as well as alcohol(Drug information on alcohol) and other drug use.^18,19

Retrospective chart reviews in patients have also suggested that patients who are switched to clozapine decrease their substance abuse. One large retrospective report of 331 patients with schizophrenia suggested that clozapine treatment decreased aggression and substance abuse, although measures of actual consumption were not presented.²⁰ A smaller study (N = 18) suggested that clozapine decreases smoking in patients in whom therapy is started with clozapine,²¹ and in a cohort of 58 patients, more than 85% of those who had substance use disorders at baseline decreased their substance use during treatment with clozapine.²²

Several comparison studies also exist. A retrospective comparison of patients treated with clozapine (n = 35) and those treated with risperidone(Drug information on risperidone) (n = 8) suggested that abstinence rates in a 1-year period were significantly higher in the group treated with clozapine (54% vs 13%),²³ although the sample size was too small to make firm conclusions and the findings need replication in larger studies. In an open-label study (N = 151), significant differences were seen in relapse rates in the 36 patients who were taking clozapine (more than 65%), compared with those taking conventional antipsychotics (34%).²⁴ A recent comparison of patients taking clozapine (n = 25) and those taking other antipsychotic medications (n = 70), all of whom were in remission from substance abuse, suggested that those taking clozapine were much less likely to relapse to substance use than were those taking other medications (8% vs 40%, respectively).²⁵

Olanzapine
After clozapine, olanzapine(Drug information on olanzapine) is the atypical antipsychotic most studied for its effects on patients with substance use disorders (perhaps because its neuropharmacologic profile has been thought to be consistent with a potentially useful medication for stimulant use disorders).²⁶ Laboratory studies have suggested that olanzapine suppresses cocaine self-administration in non-human primates²⁶ and prevents amphetamine place preference (an animal model to test the subjective effects of the drug) in rodents.²⁷ Laboratory evaluation in healthy humans suggested that olanzapine decreases cue-induced craving for tobacco.²⁸ However, in patients without comorbid schizophrenia, results of a placebo-controlled study of olanzapine for cocaine dependence were not encouraging.²⁹

In patients with schizophrenia, case reports have suggested that olanzapine decreases cocaine use.^30,31 However, these findings need confirmation in randomized, double-blind, placebo-controlled studies. In an open-label study, 30 patients taking conventional antipsychotics who abused cocaine and alcohol were treated with olanzapine. Most patients decreased substance use in general; 100% were in remission from cocaine use.³² A study comparing patients who were switched to olanzapine (n = 105) with those who continued to take conventional antipsychotics (n = 49) found that while patients who switched to olanzapine decreased substance abuse from baseline, there were no significant group differences in substance abuse outcomes.³³ In addition, patients randomized to olanzapine (n = 16) had significantly lower measures of cocaine craving than did those randomized to haloperidol(Drug information on haloperidol) (n = 15), but there were no significant differences in urine toxicology screens between groups.³⁴

Other atypicals
A few case reports and pilot studies have been published on the use of risperidone and quetiapine. Open-label risperidone was found to decrease cocaine craving and relapse rates in a small pilot study (N = 18).³⁵ In an open comparison study, those who were randomized to long-acting injectable risperidone (n = 57) had fewer positive urine toxicology screen results than did those who were randomized to depot zuclopenthixol(Drug information on zuclopenthixol) (n = 58).³⁶

As mentioned above, in a comparison with clozapine, patients treated with risperidone had worse substance abuse outcomes.³⁷ Case reports³⁸ and open- label studies have suggested that quetiapine may decrease drug use in patients with schizophrenia³⁹ and bipolar disorder⁴⁰; however, these findings must be replicated in controlled studies. Patients with schizophrenia and co-occurring cocaine dependence and alcohol abuse decreased drug use as well as cravings for drugs and alcohol with open-label aripiprazole(Drug information on aripiprazole).⁴¹