Gambling disorder (GD) is a psychiatric condition associated with both social and family costs; DSM-5 currently includes GD among addictive disorders. Despite the high burden of this condition, to date there are no treatment guidelines approved by Food and Drug Administration (FDA). Purpose of this paper is to offer a qualitative overview about the different pharmacologic agents used for the treatment of GD. Our analysis, conducted on a final selection of 75 scientific papers, demonstrates that a variety of pharmaceutical classes have been utilised, with different results. Published data, although limited by brief duration of the studies and small number of enrolled subjects, shows mixed evidence for serotonergic antidepressants, opioid antagonists, and mood stabilizers. Other compounds, such as glutamatergic agents and psychostimulants, deserve further studies.
Gambling disorder (GD) or pathological gambling is a psychiatric condition characterized by persistent and recurrent maladaptive gambling behaviour. Gambling disorder affects 0.2–5.3% of adults worldwide; the devastating consequences of this behavioural disturbance often entail severe damage to the lives of patients and their families. Previously considered among impulse control disorders, the new DSM-5 considers GD as a behavioural addiction, sharing neurobiological and clinical similarities with substance use disorders [
GD is classified under the “Addictive Disorders” section, reflecting the common substrate of addiction and highlighting recent finding on its pathophysiology and treatment. In addition, like substance-related disorders, GD presents phenomena of tolerance, withdrawal, and craving. Its onset is usually in early adolescence in men and between the ages of 20 and 40 years in women [
Pathological gamblers show specific temperamental and character dimensions as novelty seeking (NS) and self-transcendence (ST), with a growing dependence on gambling, an increase in the frequency and time spent playing, a rise in the amount of money spent attempting to recover from financial losses (e.g., investing more than the budget allows by borrowing money), and a neglect of the commitments that life requires. GD patients suffer a significant impairment in social and professional functioning [
The majority of pathological gamblers do not seek treatment: most commonly, in fact, there are family members pressuring the affected relative in order to start a therapy.
Although GD is a frequent disorder that can significantly compromise patients’ quality of life, nowadays there are no treatment guidelines approved by the Food and Drug Administration (FDA). Therefore, pharmacologic therapies should be focused on clinical dimensions (i.e., impulsivity, compulsivity, and anhedonia) or on the contingent comorbid psychiatric disorders and individualised in relation to the specific characteristics of the patient [
In recent years, several controlled clinical trials have been conducted on a variety of pharmaceutical classes, establishing an evidence-based background for the disease [
The aim of this paper is to review the role of different pharmacologic agents used for the treatment of GD, in order to help guide clinical decisions according to latest data.
We searched PubMed (
The search was conducted on October 16th, 2013, and yielded a total of 398 results. By reading titles and abstracts we excluded 323 articles from total records, in order to consider available abstracts and clinical and pharmacological trials. The full texts of the remaining 75 papers have been analysed to perform a qualitative synthesis, reported in this overview. In addition, we have searched Scopus, Google Scholar, and PsychInfo to identify any other study missed by the previous analysis. No further study has been evidenced using the same keywords.
The different pharmacological approaches currently considered for GD derive from the main psychopathological and phenomenological perspectives of the disorder itself. In fact, GD may be considered as belonging to the obsessive-compulsive disorder spectrum, as a behavioural addiction or as the result of an emotional dysregulation closely related to mood disorders [
In the first case, pharmacological approach is based on antiobsessive or antidepressant drugs, in order to improve serotoninergic transmission. Drug dose is usually medium-high and the treatment lasts longer than in depression. Controlled trials have shown positive results, in particular for fluvoxamine, paroxetine, escitalopram, and sertraline [
According to the second perspective, the most used compounds are opioid antagonists, as in the treatment of alcoholism or other forms of addiction. In particular, controlled studies have been conducted for naltrexone and nalmefene on larger samples and with the best results [
In the third approach, therapy is based on mood stabilizers such as lithium and atypical antipsychotics, as in the treatment of resistant depression and bipolar disorder [
A variety of antidepressant drugs have been studied and tested for the treatment of GD. Controlled clinical trials have shown so far conflicting results.
Hollander et al. (2000) conducted a study on fifteen subjects (ten of them completed the study) with a mean dose of fluvoxamine of 195 mg/day versus placebo. The treatment was administered for 8 weeks for fluvoxamine and for the same length of time for placebo and suggested that fluvoxamine may be effective in the treatment of GD in short-time setting, while the early placebo efficacy appeared to diminish over time [
There are currently two conflicting studies about the efficacy of paroxetine in GD. The first one was conducted for 8 weeks on forty-five patients: twenty-three of them were treated with paroxetine (20–60 mg/day) and twenty-two with placebo; paroxetine showed better results than placebo and may therefore be effective in the treatment of gambling disorder [
Saiz-Ruiz et al. (2005) treated sixty patients with GD diagnosis in a double-blind, placebo-controlled study with flexible doses of sertraline (50 to 150 mg/day) for 6 months. The results demonstrated that the efficacy of sertraline was not significantly superior to placebo in the overall sample [
Two studies have tested the efficacy of escitalopram in the treatment of GD. A trial on thirteen gamblers with comorbid anxiety, treated with escitalopram (mean dose 25 mg/day) for 12 weeks in open-label trial and for 8 further weeks in double-blind, placebo-controlled trial, demonstrated significant superiority of escitalopram compared with placebo [
An open-label study on fifteen gamblers treated with citalopram has been published in 2002. The drug appeared to determine a statistically significant improvement on gambling behaviours, depressive symptoms, and quality of life of subjects [
A study on thirty-nine patients tested the efficacy of bupropion (mean dose 325 mg/day) versus placebo in the treatment of GD; results indicated that bupropion does not have an efficacy significantly superior to placebo [
Antidepressants in gambling disorder.
Study | Drug tested and mean-range dosage | Study design | Study group and duration | Findings |
---|---|---|---|---|
Antidepressants in GD | ||||
Hollander et al. 2000 [ |
Fluvoxamine (SSRI) |
Double-blind cross-over |
15 patients |
Fluvoxamine is superior to placebo |
Blanco et al. 2002 [ |
Fluvoxamine (SSRI) |
Double-blind |
32 patients |
Fluvoxamine is not significantly superior to placebo |
Kim et al. 2002 [ |
Paroxetine (SSRI) |
Double-blind |
45 patients |
Paroxetine is superior to placebo |
Grant and Potenza 2003 [ |
Paroxetine (SSRI) |
Double-blind |
76 patients |
Paroxetine is not significantly superior to placebo |
Saiz-Ruiz et al. 2005 [ |
Sertraline (SSRI) |
Double-blind |
60 patients |
Sertraline is not significantly superior to placebo |
Grant et al. 2006 [ |
Escitalopram (SSRI) |
Open-label |
13 patients |
Escitalopram is superior to placebo |
Black et al. 2007 [ |
Bupropion (NDRI) |
Double-blind |
39 patients |
Bupropion is not significantly superior to placebo |
A growing interest has been addressed to the opioid system in the treatment of GD. Several studies have been conducted to test the efficacy of opioid antagonists in the treatment of the disorder, showing a reduction of urges to engage in the addictive behaviour and longer periods of abstinence [
In a 12-week double-blind, placebo-controlled study on forty-five GD subjects, naltrexone (
Nalmefene, another opioid antagonist, has shown promising results in the treatment of GD as well. A 16-week, randomized, dose-ranging, double-blind, placebo-controlled trial was conducted randomly assigning two hundred and seven patients to a nalmefene (25 mg/day, 50 mg/day, or 100 mg/day) or placebo treatment group. Subjects who received nalmefene had a statistically significant reduction in the severity of GD [
Finally, a double-blind and placebo-controlled trial by Grant et al. was conducted on two hundred and eighty-four subjects, treated either for 16 weeks with nalmefene (50–100 mg/day) or for 18 weeks with naltrexone (100–150 mg/day); results showed that a family history of alcoholism appeared to predict response to opiate antagonists in GD [
Opioid antagonists in gambling disorder.
Study | Drug tested and mean-range dosage | Study design | Study group and duration | Findings |
---|---|---|---|---|
Opioid antagonists in GD | ||||
Kim et al. 2001 [ |
Naltrexone |
Double-blind |
89 patients |
Naltrexone is significantly superior to placebo |
Grant et al. 2008 [ |
Naltrexone |
Double-blind |
77 patients |
Naltrexone is significantly superior to placebo |
Toneatto et al. 2009 [ |
Naltrexone |
Double-blind |
52 patients |
Naltrexone is not significantly superior to placebo |
Grant et al. 2006 [ |
Nalmefene |
Double-blind |
207 patients |
Nalmefene is significantly superior to placebo |
Grant et al. 2010 [ |
Nalmefene |
Single-blind |
233 patients |
Nalmefene 40 mg/day is significantly superior to placebo |
Mood stabilizers showed anti-impulsive properties as well as efficacy in reducing craving and preventing relapse in different substance-related disorders. Several studies have been conducted to evaluate their usefulness in the treatment of GD, also in bipolar spectrum [
Forty pathological gamblers with comorbid bipolar spectrum disorders were evaluated for 10 weeks in a randomized, double-blind, placebo-controlled trial with sustained-release lithium carbonate (mean dose 1170 mg/day), showing that lithium may be an effective treatment in reducing both gambling behaviour and affective instability [
A prospective work published in 2008 has tested efficacy and tolerability of extended-release carbamazepine in eight GD subjects treated for 10 weeks; results suggested that extended-release carbamazepine might be effective in treatment of gambling disorder [
Finally, in a recent study by Berlin et al. GD patients were randomized to assume either topiramate 25–300 mg/day (
Several studies have analysed efficacy of olanzapine in the treatment of GD. In a study by McElroy et al. on forty-two patients, in a double-blind, placebo-controlled trial (
Mood stabilizers and atypical antipsychotics in gambling disorder.
Study | Drug tested and mean-range dosage | Study design | Study group and duration | Findings |
---|---|---|---|---|
Mood stabilizers and atypical antipsychotics in GD | ||||
Hollander et al. 2005 [ |
Lithium carbonate |
Double-blind |
40 patients |
Lithium is significantly superior to placebo |
Berlin et al. 2013 [ |
Topiramate |
Double-blind |
42 patients |
Topiramate is not significantly superior to placebo |
McElroy et al. 2008 [ |
Olanzapine |
Double-blind |
42 patients |
Olanzapine is not significantly superior to placebo |
Fong et al. 2008 [ |
Olanzapine |
Double-blind |
23 patients |
Olanzapine is not significantly superior to placebo |
Other pharmacological agents have been tested for the treatment of GD.
Experimental evidence indicated common neurochemical substrates for GD and psychostimulants addiction. Therefore, drugs acting on psychostimulants addiction and impulsive symptoms may also be effective in impulsive GD patients [
A previous research of 2004 suggested that gambling induces effects that closely resemble psychostimulant drug effects; the study, a placebo-controlled trial with D-amphetamine (AMPH) 30 mg/day in gamblers (
Manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of addiction disorders. Growing evidence has accumulated indicating that ligands acting on glutamatergic transmission are also of potential utility in the treatment of drug addiction, as well as GD [
N-acetyl cysteine (NAC), an amino acid that seems to restore glutamate concentration in the nucleus accumbens, proved effective in reducing gambling urges and behaviour in a double-blind, controlled placebo study on twenty-seven GD subjects, highlighting an effectiveness in 59.3% of subjects [
In another open-label study on twenty-nine subjects, memantine (D-aspartate N-methyl receptor antagonist which seems to reduce the excitability of glutamate and improve impulsivity) was used, resulting in a reduction of gambling behaviours and an improved cognitive flexibility [
Given its dopaminergic and glutamatergic properties, amantadine has been studied in the treatment of GD. A double-blind study on 17 GD patients with Parkinson’s disease, randomly assigned to a therapy with amantadine 200 mg/day or placebo, demonstrated that the drug might be useful for the treatment of GD [
Acamprosate is derived from homotaurine, a nonspecific GABA agonist, and appears to work by promoting a balance between the excitatory and inhibitory neurotransmitters. Contrasting results have been reported on its use in GD treatment [
Instead, in a double-blind study of seventeen patients evaluated in order to test baclofen (mean dose of 30 mg/day) and acamprosate (mean dose of 666 mg/day) for GD treatment, results did not show any change in the occurrence of gambling behaviours for both medications [
Currently available data suggest the efficacy of different therapeutic strategies in the treatment of GD, showing that pharmacological research on this disorder may be promising. Although studies indicate some effectiveness of the three main classes of pharmacological interventions (antidepressants, opiate antagonists, and mood stabilizers), future investigations should be addressed to detect differences in outcome among specific subgroups of GD patients. While empirically validated treatments for GD have varying degrees of support, little is known about their mechanisms of action or how specific therapies might work better for specific individuals. In clinical practice, clinicians are accustomed to using combinations of different drugs, in particular to address the comorbid conditions, such as major depression, bipolar disorder, and substance-related disorders [
Combination strategies need to be studied, with the goal of providing validated therapeutic algorithms and more effective treatment strategies. In addition, results of published studies refer to a peculiar population of GD patients that requested help and treatment. Moreover, the data on long-term relapse prevention are scarce, compared to that on short-term treatment. Sample size should be expanded and the duration of the studies extended, in order to transfer the data on therapeutic efficacy to a wider population of gamblers and to evaluate the benefits in a longer-term follow-up. Therefore, future studies taking account of these shortcomings will reveal more insight in the underlying mechanisms of GD. Further studies are therefore needed to better understand the mechanisms of action of the different categories of drugs on gambling domains, the appropriate doses for the effective treatment, and the optimal pharmacological approach for GD.
The authors declare that there is no conflict of interests regarding the publication of this paper.