A double-blind, placebo-controlled trial of olanzapine for the treatment of video poker pathological gamblers

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Abstract

Emerging evidence suggests that dopaminergic and serotonergic functioning are altered in pathological gamblers; yet, there are no FDA-approved medications for pathological gambling and there have only been a limited number of clinical trials that have been conducted. Olanzapine was identified as a candidate medication for pathological gamblers because it modifies both dopaminergic and serotonergic function. Moreover, preliminary studies have shown that olanzapine effectively reduces impulsivity in other psychiatric disorders, a pharmacological target of interest for pathological gamblers. In this study, 21 pathological gamblers, whose primary gambling activity was video poker, were enrolled in a seven-week, double-blind, placebo-controlled trial. Outcome measures included self-reported urges for gambling, frequency of gambling behavior, and self-reported mood and anxiety levels. The results revealed that all study participants reported reduced levels of gambling urges, gambling behavior, and mood and anxiety symptoms. Olanzapine administration was not associated with an incremental effect versus placebo. While these findings suggest that olanzapine is not an efficacious treatment for video poker pathological gamblers, olanzapine may still be an effective treatment for a specific subset of pathological gamblers, including those with a co-occurring psychiatric disorder.

Introduction

To date, there are no FDA-approved medications for the treatment of pathological gambling (PG). The process by which potential medications have been identified for this disorder is based on one of two approaches. The first approach is based on targeting symptoms of PG that overlap with other psychiatric disorders, such as bipolar affective disorder (BAD). For instance, both BAD and PG are characterized by mood instability, and impulsivity. Secondly, pathological gambling is seen at higher rates than expected in patients with bipolar disorder who were recruited from the research and community settings (McElroy et al., 1992, Kim and Grant, 2006). Thus, it has been hypothesized that medications that are approved for the treatment of BAD, such as mood stabilizers, might also effectively resolve similar symptoms in individuals with PG.

The results of this approach have yielded limited success. For example, case reports suggested that lithium and carbamazepine might be an efficacious treatment for pathological gamblers without co-occurring bipolar disorders (Moskowitz, 1980, Pallanti et al., 2002). Additionally, Pallanti completed the first controlled trial of a mood stabilizer in non-bipolar, pathological gamblers, comparing the efficacy of lithium versus valproate, and reported that both medications effectively reduced gambling urges and gambling frequency (Pallanti et al., 2002). More recently, Hollander completed a placebo-controlled trial of sustained lithium versus placebo in PG with co-occurring bipolar disorder and showed that lithium was superior to placebo with respect to the reduction of gambling urges and cravings (Hollander et al., 2005). To date, there have been no controlled clinical trials using other classes of mood stabilizers, namely atypical antipsychotics, in pathological gamblers with or without co-occurring bipolar disorder.

The second approach by which candidate medications are identified is by utilizing data from pre-clinical studies that examine the neurochemical alterations associated with PG. Medications that might reverse or resolve these alterations are then evaluated for efficacy. For example, PG is associated with changes in the levels of serotonin metabolites in the cerebrospinal fluid (Roy and Linnoila, 1989, Potenza, 2001, Goudriaan et al., 2004). Based on this finding, a number of trials using selective serotonin reuptake inhibitors (SSRIs) have been conducted, with varying degrees of success. (Zimmerman et al., 2002, Grant and Kim, 2003, Dannon and Lowengrub, 2005).

Moreover, decreased concentrations of dopamine and increased levels of dopamine metabolites have been found in the cerebrospinal fluid of pathological gamblers, and are associated with the onset of PG (Roy and Adinoff, 1988, Shinohara and Yanagisawa, 1999). In addition, allelic variants of the genes for dopamine D2 receptors are differentially distributed among those with a family history of pathological gambling (Goudriaan et al., 2004). Finally, recent case studies in individuals with Parkinson's disease (PD) have shown that administration of dopamine agonists, which target the D3 receptor, can trigger PG in previously asymptomatic individuals (Stocchi, 2005, Gallagher et al., 2007, O'Sullivan and Lees, 2007).

Although dopaminergic function has been implicated in PG, the role is much more complex than a simple matter of having “too much” or “too little”. For instance, in a sample of pathological gamblers, Zack recently showed that administration of a dopamine antagonist, haloperidol, increased the rewarding effects of gambling and the desire to gamble (Zack and Poulos, 2007). They concluded that a dopamine agonist might be effective for pathological gamblers. In earlier work conducted by the same group, d-amphetamine was shown to increase the motivation and desire to gamble in problem gamblers (Zack and Poulos, 2004). Although seemingly contradictory, closer examination of these studies suggest that individuals with low levels of D2 receptors may be more susceptible to pharmacological manipulation, which may explain differential responses to rewards. There are no known reports of using amphetamines to treat pathological gamblers. In terms of dopamine antagonists, there are only a few published reports and no actual clinical trials, of pathological gambling responding to an atypical antipsychotic (Seedat et al., 2000, Potenza and Chambers, 2001).

Taken together, the evidence from these two approaches, suggest that a candidate medication targeting both dopaminergic and serotonergic functioning could ameliorate the symptoms of PG. Olanzapine, an atypical antipsychotic, demonstrates high affinity for both dopaminergic and serotonergic receptors (Bymaster et al., 1996). Moreover, olanzapine is FDA-approved for BAD and targets symptoms that are observed in both BAD and PG such as impulsivity (Bhana and Perry, 2001, Najt and Perez, 2007). Impulsivity is a complex concept and it can manifest in a number of different ways. Recently, Swann demonstrated that impulsivity appears differentially in depression versus manic states showing that motor impulsivity correlates with mania while non-planning impulsivity is associated with depression (Swann et al., 2007).

In addition to BAD, Olanzapine has shown preliminary efficacy in other disorders in which lack of impulse control is a key feature, such as trichotillomania, skin picking, and borderline personality disorder (Garnis-Jones and Collins, 2000, Stewart and Nejtek, 2003, Christensen, 2004, Shoja-Shafti, 2006). Each of these clinical conditions that responded to olanzapine, share phenomenological features with pathological gambling in that patients are unable to resist impulses and act without thinking about the consequences. Thus, given the available data regarding the efficacy of olanzapine, the current study was conducted to obtain data regarding the safety, tolerability, and potential efficacy of olanzapine for the treatment of pathological gambling.

Section snippets

Subjects

Recruitment began in September 1999 and enrollment was completed by March 2000. 23 participants were enrolled in the study and 21 completed the entire protocol (n = 12 placebo and n = 9 olanzapine, parallel groups design). Of those who did not meet study criteria, thirteen were not primarily video poker players, ten did not respond to attempts at contact following the initial phone call, five were eliminated because they were currently taking psychotropic medication, three were excluded due to

Demographics and baseline gambling behaviors

Table 1 includes a review of the demographic data for subjects who completed the study (n = 21). The placebo and the experimental groups did not differ at baseline with respect to demographic profile (e.g., age, education, gender, and ethnicity), response to measures of depression and anxiety, or gambling-related cravings (Table 1). Both groups were rated as moderate–severe pathological gamblers as based on SOGS and CGI-PG scores.

Gambling craving and gambling behaviors over time

No interactions were observed between study group and change in

Discussion

These results revealed that the pathological gamblers enrolled in this study consistently reported reduced gambling urges, reduced gambling behavior, and improved mood state; however, treatment with olanzapine was not associated with significantly improved outcomes over placebo. Although pathological gamblers demonstrated reduced gambling behaviors after treatment, their overall improvement, in both groups, as measured by the clinician's global impression (CGI) was minimal and not statistically

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    Study was conducted at the Trimeridian Gambling Treatment Program, Las Vegas, NV.Study was funded by an investigator-initiated project by Eli Lilly and Company, Indianapolis, IN and NIDA K2319522.A portion of these results were presented at 14th National Conference on Problem Gambling. Philadelphia, PA, October, 2000.

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