Quetiapine for the treatment of cocaine use disorder
Introduction
Cocaine use in the United States is a significant public health concern, leading to loss of income, use of public services, and mortality. The results from the 2012 National Survey on Drug Use and Health (2013) shows that 1.6 million Americans aged 12 or older were current cocaine users (including crack cocaine), comprising .6% of the population. Despite this widespread use, there are currently no approved medications for the treatment of cocaine use disorder.
Numerous psychoactive compounds, including dopamine agonists (such as psychostimulants which, like cocaine, block monoamine neurotransmitter transporters), dopamine antagonists, antidepressants, and mood stabilizers have undergone study for the treatment of cocaine use disorder. A variety of agents have shown promise in open-label trials, but few have shown efficacy in randomized controlled trials (de Lima et al., 2002, Elkashef et al., 2005). Agents that have shown some initial efficacy in randomized, controlled trials are propranolol (Elkashef et al., 2005, Kampman et al., 2001), baclofen (Shoptaw et al., 2003), and vigabatrin (Brodie et al., 2009; Somoza et al., 2013). Topiramate has had some mixed results with some studies demonstrating efficacy (Johnson et al., 2013, Kampman et al., 2004, Kampman et al., 2013) including a study in which topiramate was combined with mixed amphetamine salts (Mariani et al., 2012). Cochrane database systematic reviews have not found support for the use of dopamine agonists for the treatment of cocaine dependence (Amato et al., 2011), and have found mixed results for the efficacy of psychostimulant medications for cocaine dependence (Castells et al., 2010), with some studies finding reductions in cocaine use (Grabowski et al., 2001, Mariani and Levin, 2012, Mooney et al., 2009), and other studies finding no benefit to psychostimulants (Schmitz et al., 2012).
Since dopaminergic and serotonergic receptors may be involved in the reinforcing effects of cocaine, medications such as second generation antipsychotics that block dopamine and serotonin receptors may reduce the rewarding effects of cocaine and thus lessen cravings for cocaine. Animal studies have given support to this hypothesis (Meil and Schechter, 1997, Sorensen, 2008). Specifically, quetiapine was shown to block the reward enhancing effect of cocaine in rats (Gallo, 2010).
The research on the use of atypical antipsychotics to treat cocaine use disorder in non-psychotic individuals has reported mixed results. In cocaine challenge studies examining pretreatment with clozapine (Farren et al., 2000) and risperidone (De La Garza et al., 2005, Newton et al., 2001), results indicated the antipsychotics reduced the euphoria associated with administration of cocaine, and risperidone also reduced cravings triggered by cocaine challenge (De La Garza et al., 2005). Furthermore, in open-label trials, treatment with risperidone was found to significantly reduce cocaine cravings in non-psychotic, cocaine users (Roy et al., 1998, Smelson et al., 1997). A 20-week study of 80 patients with cocaine or methamphetamine use disorder prescribed either olanzapine or risperidone found that both medication groups had decreased drug cravings (Nejtek et al., 2008). However, two double-blind, placebo-controlled studies of risperidone for the treatment of cocaine use disorder did not find significant reductions in cocaine cravings or use (Grabowski et al., 2000, Smelson et al., 2004).
Likewise, three double-blind, placebo-controlled studies that have evaluated the efficacy of olanzapine for the treatment of cocaine use disorder did not yield positive results (Hamilton, 2009, Kampman et al., 2003, Reid et al., 2005). Studies of aripiprazole have also been mixed. A 12-week randomized trial of aripiprazole and ropinirole found that aripiprazole was effective in reducing cocaine use (Meini, 2011). However, in a human laboratory study, aripiprazole was found to actually increase self-administration of smoked cocaine (Haney et al., 2011). A meta-analysis of randomized, placebo-controlled trials of antipsychotics for cocaine or psychostimulant dependence, did not find advantages of the antipsychotics over placebo, but quetiapine was not one of the antipsychotic medications studied (Kishi et al., 2013).
Differences in mechanisms of action may render certain atypical antipsychotics more effective and safer than others for the treatment of cocaine use disorder. Theoretically, quetiapine's relatively high affinity for both alpha1 and alpha2 adrenergic receptors (Richelson and Souder, 2000) may yield improvements in mood symptoms associated with cocaine use. Three retrospective chart reviews have found reductions in cravings and alcohol use associated with quetiapine (Monnelly et al., 2004, Pinkofsky et al., 2005, Sattar et al., 2004), however, a double-blind, placebo-controlled trial of quetiapine for alcohol dependence found no significant differences between the quetiapine and placebo groups (Litten et al., 2012).
Brown et al. (2002) found a significant decrease in subjects’ cocaine cravings and an 87% reduction in the amount of money spent on cocaine in 17 outpatients with bipolar disorder and cocaine dependence who were treated with quetiapine; however, a follow-up study of 12 individuals with bipolar disorder and cocaine dependence was non-significant. Another open-label trial of quetiapine in individuals with schizophrenia found that quetiapine was associated with reductions in cocaine use (Potvin et al., 2006). Finally, our own open-label trial (Kennedy et al., 2008) examined quetiapine in 22 non-psychotic subjects with cocaine dependence over six weeks of treatment. Results found that cravings for cocaine decreased significantly over time (β = −.54; 95% CI = −.81, −.28; p < .001). A decrease in the number of grams of cocaine used was not statistically significant in the group of completers, but showed a trend toward significance (β = −.12; 95% CI = −.24, .01; p = .063). The results from this pilot study suggested that quetiapine effectively reduced cocaine cravings in non-psychotic individuals suffering cocaine use disorder.
To further investigate the hypothesis that quetiapine is efficacious for the treatment of cocaine use disorder, the authors conducted this randomized, double-blind, placebo-controlled trial to test the effectiveness of Seroquel XR™ for the treatment of cocaine use disorder in non-psychotic, community dwelling individuals. The primary objective of this study was to compare cocaine use and cravings between the quetiapine and placebo groups, leading to three hypotheses.
Hypothesis 1: The quetiapine group will have significantly more individuals who demonstrate end of trial abstinence from cocaine (defined as a negative urine drug screen for three consecutive weeks) than the placebo group.
Hypothesis 2: The quetiapine group will demonstrate significantly less cocaine use and money spent on cocaine as measured by a self-report measure than the placebo group.
Hypothesis 3: The quetiapine group will have significantly more individuals who demonstrate end of trial absence of cravings (defined as a negative self-report of cravings for three consecutive weeks) than the placebo group.
Section snippets
Participants
Participants were both Veteran and non-Veteran community participants, aged 18 to 65, who were currently (within the past 30 days) using cocaine. Potential subjects with a psychotic disorder (bipolar, schizophrenia, etc.) or who were psychiatrically or medically unstable were excluded from the study, as were women who were pregnant or nursing. Since these data were collected prior to the publication of the DSM-5, all participants met criteria for cocaine dependence, as determined by
Baseline group differences
Independent t-tests found no significant differences in age, education, years of cocaine use, or prior drug or alcohol treatment between placebo and quetiapine groups (see Table 1). Chi-square analyses indicated no difference between groups in any co-morbid diagnoses or whether or not they had ever received prior substance abuse treatment (see Table 1). There were also no significant differences between groups in terms of self-reported cocaine use or rates of negative UDS at baseline (see Table
Discussion
The quetiapine group did not show significant differences from the placebo group in terms of self-reported cocaine use, self-reported money spent on cocaine, cravings for cocaine, or urine drug screen results. Considering the large dropout rate, and the potential for type II error, intent to treat (ITT) analyses were conducted using two hypotheses. The first ITT analyses were run with the assumption that all individuals who had dropped out of the study had relapsed and returned to substance
Role of funding source
Funding for this study was provided by an investigator initiated grant from AstraZeneca Pharmaceuticals; AstraZeneca Pharmaceuticals had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
Andre Tapp, M.D. obtained the funding for the Study. He designed the study including the protocol, participated to the writing of the paper and approved the final manuscript for publication. Amanda Ernst Wood, Ph.D. helped with the study design, project coordination, and the preparation of the manuscript. Annette Kennedy helped with study design, development of the protocol, and the coordination of the project. Patrick Sylvers undertook the statistical analysis and preparation of the
Conflict of interest
Andre Tapp, M.D. has received honoraria from AstraZeneca Pharmaceuticals. All other authors declare that they have no conflicts of interest.
Acknowledgements
The authors wish to thank the following people whose contributions made this research possible: Ryan Caldeiro, M.D.; Nicolette Camancho, Tracia Clark; Lyndel Cubberley, B.S.N., A.R.N.P.-C.; Clara Doctolero, Psy.D.; Shonn Devory; Ann Goldberg; Laura Ferguson, M.D.; Vivek Jain, M.D.; Charles Meredith, M.D.; Lawrence Martin, MD; Laurie Maus; Kathy Miller, B.S.N.; Heike Pope, B.S.N.; Tanya Scurry, M.D.; Victoria Syke Sellars; and Darcy Vavrek, Ph.D.
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