Pharmacological Treatments for Disordered Gambling: A Meta-analysis

The objective of this paper was to investigate the efficacy of pharmacological treatments for disordered gambling and to identify possible predictors of treatment outcome. Results from within-group study designs revealed that pharmacological treatments effectively reduced the global severity and financial loss from gambling at short-term. We also ascertained a strong effect size for the reduction of frequency; however, the result from the trim-and-fill analysis indicated asymmetry in the underlying study sample. Although this could be caused by publication bias, it is more reasonable to assume that funnel plot asymmetry arose from between-study heterogeneity (Egger et al. 1997; Sterne et al. 2001). Furthermore, the robustness of the treatment effect to reduce gambling frequency is supported by the fail-safe N analysis. Treatment success for the reduction of global severity remained stable over longer periods; however no firm conclusions can be drawn on the long-term gains of pharmacological treatments for the remaining outcome variables due to the limited amount of data. Similar levels of short-term effect sizes and the lack of catamnestic data were reported in previous meta-analyses in this area (Leibetseder et al. 2011; Pallesen et al. 2007). Direct comparisons with the present meta-analysis, however, are problematic because effect sizes were pooled across within-group and controlled study designs.

As expected, inferior results for medications were observed in controlled study designs suggesting high rates of placebo responses. A number of reasons might account for these findings. First, mediators such as the therapeutic alliance established by regular contacts between patients and therapists, patients` expectations to benefit from treatment, learning processes associated with drug stimuli (classical conditioning), elevated levels of motivation to change problematic behavior, or the natural recovery from gambling, all aspects which are extensively discussed in the literature (e.g., Finniss et al. 2010; Grant and Chamberlain 2017; Prochaska et al. 1992; Schedlowski et al. 2015; Slutske 2006), may have contributed to the small between-group differences. Alternatively, additional support (i.e., keeping diaries, participation in Gamblers Anonymous groups, or self-help programs) which was either recommended or not monitored in some trials may have influenced the treatment effects. Despite these limitations, we ascertained significant medium and small benefits of medications relative to placebo for reducing the global severity and financial loss from gambling. Except for the overall effect size for the global symptom severity, however, our results should be interpreted with caution due to the lack of robustness demonstrating the need for further research. Nevertheless, the magnitude of the effect for the global symptom severity corresponds to that found for a variety of medical diseases and mental health disorders revealing a median of all effect sizes of 0.40 (Leucht et al. 2012). As observed across both study designs, the implementation of short, one-week placebo lead-in phases did not affect treatment response. In the light of an early and high placebo effect observed for disordered gambling (Hollander et al. 1998, 2000), more extended run-in phases may lead to a more effective identification of placebo responders.

Moderator analyses indicated a small and nonsignificant advantage of combined treatments over pharmacotherapy alone for the reduction of global severity in within-group study designs and the reduction of financial loss in controlled study designs partially supporting our hypothesis. Although our findings were based on a limited number of combined trials, they agree with the tendency found in a recent review of meta-analyses on a range of medical diseases and disabling conditions (Huhn et al. 2014). With regard to the limitations of placebo controlled designs, it should be noted that particularly combined treatments examining medications along with psychotherapies which were equally provided to the placebo groups appear susceptible for masking the drug effect (Kovanen et al. 2016). Therefore, separate treatment groups receiving medication and psychotherapy alone compared with the combined treatment may help to disentangle the efficacies of the relevant treatment elements in upcoming studies (see also De Brito et al. 2017; Kovanen et al. 2016).

Improvement was independent from treatment duration and gambling type across both study designs. The latter finding agrees with that reported in meta-analyses on psychological treatments for disordered gambling (Gooding and Tarrier 2009; Goslar et al. 2017) suggesting that all gamblers may share common mechanisms of addiction which were reduced during treatment. Moreover, individuals with and without co-occurring mood disorders and/or anxiety benefited to a comparable degree from treatment underscoring the conclusions of a recent review (Dowling et al. 2016). Only lithium appeared to be most effective for gamblers with bipolar disorder (Hollander et al. 2005a) supporting the treatment algorithm for this subgroup of individuals (Bullock and Potenza 2012). Given the preliminary nature of these results, future studies should systematically investigate and report the types and rates of co-occurring disorders in order to identify subgroups of gamblers, and to determine the impact of comorbidity on treatment outcomes (Dowling et al. 2016). Similarly, we found no advantage of any medication class over the other in reducing symptoms of disordered gambling across both study designs (see also Bartley and Bloch 2013; Pallesen et al. 2007). Regarding within-group study designs, however, agomelatine outperformed SSRIs, SNDRI and NDRI. This novel antidepressant that promotes the resynchronization of circadian rhythms by acting on melatonin and 5-HT_2c receptors (Le Strat and Gorwood 2008) produced promising results in the treatment of mood, anxiety, and a range of other disorders (for a review see De Berardis et al. 2015). Since our findings were based on a single trial including a small number of participants (Egorov 2017), further research is required to substantiate the efficacy of agomelatine for the treatment of disordered gambling. The particularly large effect size of this study and the beneficial gains of recently published treatments on topiramate (De Brito et al. 2017), naltrexone (Kovanen et al. 2016), N-acetylcysteine (Grant et al. 2007; Grant et al. 2014b), and ecopipam (Grant et al. 2014a) may have caused the positive association between outcome and year of publication and the superiority of flexible over fixed dosage regimen for the reduction of global severity. Although a slight advantage for flexible dosage was found for the remaining outcome variables, results should be interpreted with caution and warrant further research.

Also in line with the current state of knowledge emphasizing opioid antagonists as the most supported drug treatment for gambling disorder (Bartley and Bloch 2013; Bullock and Potenza 2012), we ascertained a significant and medium advantage of opioid antagonists over placebo for the reduction of global severity. In contrast to Bartley and Bloch (2013), however, who found substantial heterogeneity across the studies and an effect size being flawed by the type of data analysis and the year of publication, our analyses revealed between-study homogeneity with no moderators impacting the effect size for opioid antagonists. These differences may be based on the fact that Bartley and Bloch (2013) pooled effect sizes across scales with different contents (i.e., global severity, frequency and financial loss were subsumed under the single outcome variable “gambling severity”), and across varying measurement tools. Therefore, future studies and meta-analyses are encouraged to select equivalent response measures and differentiate between distinct aspects of gambling behaviors as recommended by the Banff, Alberta Consensus (Walker et al. 2006) in order to collect more information about the impact of treatment on frequency and financial loss from gambling, and to facilitate comparisons across the studies (for a review see Pickering and Keen 2018). Besides opioid antagonists which proved effective not only for the treatment of alcohol dependence (e.g., Jonas et al. 2014), but also for behavioral addictions other than disordered gambling (for a review see Mouaffak et al. 2017), we observed significant superiority of mood stabilizers over placebo supporting our hypothesis. It should be noted, however, that these results were driven by single trials which produced strong effects including either gamblers with bipolar disorders treated with lithium (Hollander et al. 2005a), or those treated with topiramate coupled with a brief cognitive intervention (De Brito et al. 2017; see Fig. 2 for the reduction of financial loss). In addition to topiramate, other glutamatergic agents such as N-acetylcysteine and acamprosate which are favorable treatment options for substance use disorders (Guglielmo et al. 2015; Minarini et al. 2017; Witkiewitz et al. 2012), produced promising results in noncontrolled trials for disordered gambling (Black et al. 2011; Grant et al. 2007). Since medications targeting glutamatergic pathways not only appear to reduce symptoms of craving, but may also enhance cognitive flexibility as demonstrated by the use of memantine (Grant et al. 2010a), these types of drugs seem promising for investigation in further controlled study designs (Pettorruso et al. 2014). Relative to placebo, antidepressants reduced the global symptom severity to a similar level compared to that of the remaining drugs. The lack to obtain a significant effect, however, may be due to the heterogeneity across the studies caused by a single trial that determined the magnitude of the treatment response and differed from the others by yielding a large effect size and including a high percentage of female participants (Kim et al. 2002). Even though a variety of gender-specific differences were ascertained in clinical trials (e.g., Echeburua et al. 2011), the impact of sex on treatment outcomes needs to be replicated. Moreover, antidepressants may act differentially for subgroups of gamblers with additional diagnoses other than mood disorders and/or anxiety which were not systematically assessed. For example, SSRIs may be beneficial for gamblers with obsessive–compulsive disorders, but not for individuals with attention-deficit/hyperactivity disorder (Hollander et al. 2005b) underpinning the need to investigate comorbid conditions (Dowling et al. 2016).

Nevertheless, some limitations and implications for further research should be mentioned: First and foremost, our meta-analysis covered a small number of studies. However, the short-term within-group effect sizes, and the overall controlled effect size for the reduction of global severity were robust. Second, as is true for most meta-analytic reviews, the included studies differed in their methodological quality, although when addressed statistically, we did not observe a systematic bias in the effect sizes due to differences in the quality of the studies. It should be noted that none of the studies achieved the highest rating reflecting limited quality of evidence with respect to selection bias, high dropout rates, and—particularly regarding within-group study designs—to the identification and control of confounders, and blinding. As a result, rigorously designed, large-scale RCTs are necessary including extended placebo lead-in periods, the monitoring of additional psychosocial support, the type of comorbidity, the use of equivalent measurement tools, the reporting of outcome variables according to the Banff, Alberta Consensus (Walker et al. 2004), and the provision of follow-up data in order to determine the efficacy of medications over the long-term. Although the amount of drug dosage has demonstrated to impact treatment outcome (e.g., Bloch et al. 2010), this moderator could not be addressed in the present meta-analysis, because the studies often provided insufficient information. Furthermore, when this information was provided, the dosage often varied depending on the type of medication, complicating these analyses, which would have resulted in insufficient test power. Moreover, the dosage within each drug class usually showed little variation, further complicating these analyses (Thompson and Higgins 2002). Therefore, additional studies will be necessary to examine the impact of dosage on treatment outcome within the different drug classes. Moreover, separate data should be reported for participants who receive low, moderate or high doses of the relevant medication facilitating the comparability of dosage within each drug class.

Despite these limitations, the results of the present meta-analysis suggest that a variety of medications are effective for the management of gambling behaviors. Focusing placebo controlled designs, opioid antagonists and mood stabilizers, particularly the glutamatergic agent topiramate combined with a cognitive intervention and lithium for gamblers with bipolar disorders demonstrated preliminary evidence for reducing the global gambling severity. Although further neurobiological and neuroimaging studies should promote a better understanding in the mechanisms underlying problematic gambling behavior (e.g., Bullock and Potenza 2012), it seems most important to investigate the reasons for the high placebo response rates (Grant and Chamberlain 2017) and the natural recovery (e.g., Cuijpers and Cristea 2015) in order to improve pharmacological treatments for disordered gambling.