Treatment modalities for patients with gambling disorder

Gambling disorder (GD) is defined as “persistent and recurrent problematic gambling behavior leading to clinically significant impairment or distress.” [1] Unlike the long history of substance addiction, GD has rarely been studied as a disease [2]. The American Psychiatric Association regarded “pathological gambling” as an impulse control disorder in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [3]. In DSM-5, the most recent version, pathological gambling was re-categorized into the group of substance-related and addictive disorders and renamed GD [1]. This diagnostic change reflects longstanding conceptualizations of GD as an addiction [4].

Generally, the prevalence of GD has been shown to be 1.2–7.1% in the general population [5]. GD can severely impact on personal and vocational wellbeing as well as lead to financial problems [6, 7]. In addition, GD presents many psychiatric comorbidities such as depressive disorder, antisocial personality disorder, anxiety disorder, attention deficit hyperactivity disorder, and substance-related disorders [8, 9]. GD also can be associated with death due to suicide [10]. Various marketing tactics that gambling industry use recently may promote gambling problems [11, 12]. In South Korea, GD has become an important social problem. A national survey of 20,000 individuals from the general population reported that 5.4% had gambling problems [13]. The social costs of gambling are estimated to be over 11 trillion South Korean Won (KRW) (about 10 billion USD) per year [13].

To address these problems and social costs, effective interventions for GD patients are necessary. However, GD is notoriously difficult to treat, as it is a chronic relapsing disorder with high treatment dropout rates [14]. Therefore, we believe that clinicians need to pay more attention to the treatment of GD. Treatment modalities for GD have generally been classified into two categories: pharmacotherapy and psychosocial treatments [15]. Pharmacotherapy includes not only anti-craving agents but also antidepressants and mood stabilizers. Group/individual cognitive behavioral therapy (CBT), motivational interviewing (MI), and Gamblers Anonymous (GA) are examples of psychosocial treatments [10]. In this review, we describe pharmacotherapy/psychosocial treatments currently available, and summarize data on the effectiveness of these GD treatments. In addition, we also introduce more recently tested treatment modalities. We refer to newly as well as previously published studies and guidelines, and conclude with recommendations for future research.

No medication has received Food and Drug Administration approval as a treatment for GD to date [16]. However, pharmacotherapy can have positive effects on GD patients such as reduction of urge, treatment of comorbidities, and relapse in prevention [15]. Medications frequently used to treat GD are opioid receptor antagonists, selective serotonin reuptake inhibitors (SSRIs), and mood stabilizers.

Opioid receptor antagonists have been used in the management of alcohol and drug dependent patients for several decades [17, 18]. Also in GD, these medications can diminish urges to engage in gambling and increase the periods of abstinence by modulating the effects of the arcuate nucleus opioid neurons on the ventral tegmental area and mesolimbic dopamine circuitry [19, 20]. A recent meta-analysis study showed that, compared to placebo, only opioid receptor antagonists demonstrated significant benefit in the pharmacological treatment of GD. However, this result provided only limited support due to its methodology [21]. Opioid receptor antagonists include naltrexone and nalmefene. In 2001, the first double-blind placebo-controlled study on the efficacy of naltrexone in GD was published [22]. This study involved an 18-week trial and showed that naltrexone is effective in reducing the intensity of urges to gamble, gambling thoughts, and gambling behavior. The efficacy of naltrexone was especially high in individuals with higher intensity of gambling urges. In this study, the mean daily dose of naltrexone was 188 mg, and many individuals reported side effects such as nausea, dry mouth, and vivid dreams. Grant et al. replicated these findings in a larger study [23]. They suggested that a dose of 50 mg of naltrexone was sufficient and associated with fewer side effects. In addition, one study reported that the positive effect of naltrexone may persist after discontinuation [24]. Naltrexone has also been shown to be effective in GD patients with Parkinson’s disease already treated with dopamine agonists [25]. On the other hand, Kobanen et al. tried to verify the effect of as-needed naltrexone through a randomized, double-blind, placebo-controlled trial [26]. They instructed participants to take one capsule always in an as-needed manner when planning to gamble or when experiencing a strong urge to gamble (preferably 30–60 min before gambling), but the rates of response did not differ between groups. Two large double-blind placebo-controlled studies reported that nalmefene demonstrated superior efficacy than placebo in treatment outcomes for GD [20, 27]. These studies suggested that 25, 40, and 50 mg of nalmefene were effective but higher doses increased side effects such as nausea.

SSRIs were one of the first medication types tested for treating GD. Several studies reported that fluvoxamine was effective in the treatment of GD [28‐30]. The treatment duration in these studies was 8 or 12 weeks, and the maximum doses of fluvoxamine were 200 or 250 mg. However, another study on fluvoxamine treatment in GD patients did not reach statistical significance [31]. In addition, Dannon et al. conducted a 6-month follow-up study for fluvoxamine responders who discontinued their medication [24]. They reported that three of six fluvoxamine responders relapsed. On the other hand, paroxetine was reported to be superior to placebo in one trial, but not in another. Kim et al. conducted a double-blind placebo-controlled trial, and showed the efficacy of paroxetine in the treatment of GD [32]. The mean doses of paroxetine were 51.7 mg, and adverse events were minimal. Nevertheless, another double-blind placebo-controlled trial reported that the paroxetine group showed larger improvements than the placebo group, but not at a significant level [33]. Furthermore, one open-label trial suggested that escitalopram was effective in the treatment of GD [34]. Another study also found a significant improvement in individuals with GD and co-occurring anxiety disorders [35]. However, further double-blind, placebo-controlled studies should be performed to support this result. In the case of sertraline, one double-blind placebo-controlled study was conducted to verify its efficacy, but the authors failed to draw significant results [36]. There is a controversy about whether SSRIs can reduce urges to gamble, but they can treat the anxiety and depressive symptoms of GD patients. In turn, this may reduce gambling behavior in patients who gamble to avoid anxiety and depression [15]. Additional double-blind placebo-controlled studies involving larger samples are needed to verify the efficacy of SSRIs more clearly. In addition, there was a tendency to require relatively high doses and long treatment duration for effective SSRI treatment of GD. Thus, future studies also need to focus on identifying optimal doses and treatment duration of SSRIs.

Mood stabilizers have also been used to treat GD. Hollander et al. conducted a double-blind placebo-controlled trial enrolling individuals with GD and bipolar-spectrum disorders to investigate the efficacy of lithium [37]. The authors found that the lithium group showed significantly less severe gambling urges and behavior than did the placebo group. On the other hand, one single-blind study compared lithium and valproate treatments in GD patients [38]. Both the lithium and valproate groups showed a significant improvement with similar efficacy, but the small sample size, single-blind design, and lack of placebo control were limitations of this study. Black et al. tested carbamazepine in the treatment of GD and reported a significant improvement [39]. However, this study provided limited evidence because of its open-label setting, small sample size, and lack of placebo control. One double-blind placebo-controlled trial showed that topiramate reduced impulsivity in GD patients but was not superior to placebo in reducing gambling urges and behavior [40]. On the other hand, a recent double-blind placebo-controlled study reported that topiramate proved to be superior to placebo in reducing gambling craving, time and money spent gambling, cognitive distortions related to gambling, and social difficulties [41]. However, this study used a brief cognitive intervention as well as topiramate or placebo; therefore, the results could be due to a synergistic intervention. The efficacy of mood stabilizers in GD has been investigated mainly in specific settings such as comorbidity with bipolar disorder; thus, more studies are needed to verify their efficacy.

Besides the abovementioned pharmacotherapies, various medications have been investigated in the treatment of GD patients. Bupropion has been used to treat various addictive disorders [42, 43]. Dannon et al. conducted a blind-rater study comparing GD subjects taking naltrexone and bupropion, and reported that the efficacy of bupropion was similar to that of naltrexone [44]. However, the first and only double-blind placebo-controlled trial examining bupropion showed that it was not superior to placebo in the treatment of GD [45]. Olanzapine has been evaluated in two double-blind, placebo-controlled trials, but both studies failed to show differences between olanzapine and placebo in the treatment of GD [46, 47]. In addition, Grant et al. reported the efficacy of as-needed ecopipam on GD patients in single-blind setting. However, more controlled studies are required to support this result [48]. On the other hand, one study reported that haloperidol actually promoted gambling-related thoughts and behaviors [49]. Zack and Poulos tested modafinil with GD patients in a double-blind, placebo-controlled setting [50]. They reported that modafinil decreased motivation to gamble and risky decision making, and improved inhibitory control in high-impulsivity participants; however, it had opposite effects on low-impulsivity participants. Another analysis showed that modafinil might deter pathological gamblers from chasing losses but also encourage them to continue betting rather than quit while they are ahead [51]. N-acetyl cysteine (NAC) was found to be effective in the treatment of GD patients in one open-label trial with a double-blind discontinuation period [52]. However, there were some limitations to this study such as small sample size, short duration of treatment, and the fact that only responders were randomized into the double-blind portion of the study. One double-blind, placebo-controlled trial tested NAC in individuals with co-occurring nicotine dependence and GD who were receiving imaginal desensitization therapy for GD and found that NAC presented additional benefits at 3-month follow-up [53]. Amantadine was shown to decrease GD symptoms among GD individuals with Parkinson’s disease in a double-blind, placebo-controlled trial [54]. A recent study also reported that GD participants with Parkinson’s disease showed a decrease in risky choices and an increase in non-risky choices during amantadine treatment [55]. On the other hand, another study found that amantadine use could be associated with GD in Parkinson’s disease patients [56]. One open-label study tested memantine in GD patients and reported that memantine treatment was associated with diminished gambling and improved cognitive flexibility [57]. However, this study provided limited evidence because of small sample size, short-term follow-up duration, and open-label setting. In two open-label trials, acamprosate has also been tested for GD patients. However, the result of each trial is conflicting [58, 59]. The efficacy of most of these medications to treat GD has not yet been definitely confirmed. Some of them have proved to be effective in only specific situations. In addition, a few of them were even found to exacerbate the symptoms of GD. Therefore, clinicians should be careful when prescribing these medications to GD patients.