Treatment discontinuation in pharmacological clinical trials for gambling disorder.

BACKGROUND: Gambling disorder affects 0.5-2% of the population, and of those who receive treatment, dropout tends to be relatively high. Very little is known about participant-specific variables linked to treatment discontinuation/dropout in gambling disorder, especially in pharmacological clinical trial settings. METHODS: Data were pooled from eight previous randomized, controlled pharmacological clinical trials conducted in people with gambling disorder. Demographic and clinical variables were compared between those who did versus did not subsequently dropout from those treatment trials. RESULTS: The sample comprised data from 635 individuals, and the overall rate of treatment dropout was 40%. Subsequent treatment dropout was significantly associated with the following: positive family history of gambling disorder in one or more first degree relatives (relative risk [RR] of dropout in those with positive history vs not = 1.30), preference for mainly strategic vs non-strategic gambling activities (RR = 1.43), lower levels of education (Cohen's D = 0.22), and higher levels of functional disability (Cohen's D = 0.18). These variables did not differ significantly as a function of treatment condition (medication versus placebo). Dropouts and completers did not differ significantly in terms of the other demographic or clinical variables that were considered. CONCLUSIONS: This study identified several candidate participant-specific predictors of pharmacological treatment dropout in gambling disorder. The findings highlight the need for future studies to address a wider range of contextual variables at large scale (including also study-specific variables e.g. trial/intervention duration), including in naturalistic treatment and clinical trial settings, with a view to developing algorithms that might usefully predict dropout risk.

Silymarin (Milk Thistle) Treatment of Adults With Gambling Disorder: A Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Data on the pharmacological treatment of gambling disorder are limited. Silymarin (derived from milk thistle) has antioxidant properties. The goal of the current study was to determine the efficacy and tolerability of silymarin in adults with gambling disorder. METHODS: Forty-three individuals (18 [41.9%] women; mean age=49.61 [±13.1] years) with gambling disorder entered an 8-week, double-blind, placebo-controlled study. Dosing of silymarin ranged from 150 to 300 mg twice a day. The primary outcome measure was the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS). Secondary outcome measures comprised the Gambling Symptom Assessment Scale and measures of depression and anxiety. Outcomes were examined using mixed-effect models. RESULTS: Silymarin did not statistically differentiate from the placebo on any of the outcome measures of interest, in terms of treatment group×time interactions. There was a robust response in the placebo group (57% reduction on the PG-YBOCS), and on average there was a 56% reduction in YBOCS score for the milk thistle. CONCLUSIONS: The findings of this study do not support the use of silymarin/milk thistle in the treatment of gambling disorder but highlight the large placebo response seen in gambling disorder. Treatment interventions for gambling disorder need to better understand and address the placebo response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02337634.

Pharmacological management of gambling disorder: an update of the literature.

INTRODUCTION: Gambling disorder (GD) is a mental health condition characterized by persistent and problematic betting behavior. GD generates distress and impairment, and treatment options include psychological and pharmacological interventions. AREAS COVERED: This narrative review explores existing pharmacological treatments for GD. The following classes of medications were considered: opioid-receptor antagonists (e.g. naltrexone and nalmefene), serotonin reuptake inhibitors (e.g. fluvoxamine, paroxetine, sertraline, escitalopram, and citalopram), glutamatergic agents (e.g. N-acetylcysteine (NAC), acamprosate, and memantine), mood stabilizers (e.g. topiramate, carbamazepine, lithium), and other medications (e.g. modafinil, nefazodone, olanzapine, haloperidol, tolcapone, and bupropion). EXPERT OPINION: Due to the limitations of the studies reviewed, solid conclusions regarding the optimal choice of pharmacotherapy for individuals with GD are challenging to draw at this time. Despite some medications, such as naltrexone and nalmefene, showing promising results, efficacy has varied across studies. The review highlights current gaps/limitations, including small sample sizes, limited diversity in participant demographics, the need for exploring different gambling subtypes and treatment responses, high placebo response rates, lack of longer-term longitudinal information, limited investigation of neurobiological correlates and co-occurring disorders, and the importance of implementation research. Further research is needed to address these gaps and explore additional medications, as well as interventions like neuromodulation.

The pharmacological management of gambling disorder: if, when, and how.

INTRODUCTION: Gambling disorder (GD) consists of a persistent, recurrent pattern of gambling that is associated with substantial distress or impairment. The etiology is multifactorial. GD frequently co-occurs with other psychiatric disorders and is often untreated. Different psychosocial interventions, particularly cognitive-behavioral therapy, are useful in the treatment of GD. Pharmacological therapy may also be helpful . No formal guidelines exist, and the management of the disease is often guided by few clinical elements. AREAS COVERED: A literature search was performed using PubMed, Scopus, and Web of Science databases about treatment options for GD, considering both psychosocial treatments and available pharmacological ones. EXPERT OPINION: The authors address whether and when it is appropriate to initiate pharmacological treatment for GD. They focus on providing clinicians with guidance on how to approach patients with GD in those situations where pharmacological therapy may be necessary. The reasons for the clinician to start thinking about a medication are examined. As specific traits in the psychopathology of GD may be managed with a strategic choice of the pharmacologic agent, the different available options are analyzed on the basis of their potential usefulness in GD. Issues that remain open about the pharmacological management of GD are summarized.

Pharmacological interventions for the treatment of disordered and problem gambling.

BACKGROUND: Pharmacological interventions for disordered and problem gambling have been employed in clinical practice. Despite the availability of several reviews of the efficacy of pharmacological interventions for disordered or problem gambling, few have employed systematic search strategies or compared different categories of pharmacological interventions. Systematic reviews of high-quality evidence are therefore essential to provide guidance regarding the efficacy of different pharmacological interventions for disordered or problem gambling. OBJECTIVES: The primary aims of the review were to: (1) examine the efficacy of major categories of pharmacological-only interventions (antidepressants, opioid antagonists, mood stabilisers, atypical antipsychotics) for disordered or problem gambling, relative to placebo control conditions; and (2) examine the efficacy of these major categories relative to each other.  SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase, and PsycINFO (all years to 11 January 2022). SELECTION CRITERIA: We included randomised trials evaluating a pharmacological intervention for the treatment of disordered or problem gambling. Eligible control conditions included placebo control groups or comparisons with another category of pharmacological intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures, including systematic extraction of included study characteristics and results and risk of bias assessment. Our primary outcome was reduction in gambling symptom severity. Our secondary outcomes were reduction in gambling expenditure, gambling frequency, time spent gambling, depressive symptoms, anxiety symptoms, and functional impairment; and responder status. We evaluated treatment effects for continuous and dichotomous outcomes using standardised mean difference (SMD) and risk ratios (RR), respectively, employing random-effects meta-analyses. A minimum of two independent treatment effects were required for a meta-analysis to be conducted (with only meta-analytic findings reported in this abstract). MAIN RESULTS: We included 17 studies in the review (n = 1193 randomised) that reported outcome data scheduled for end of treatment. Length of treatment ranged from 7 to 96 weeks.  Antidepressants: Six studies (n = 268) evaluated antidepressants, with very low to low certainty evidence suggesting that antidepressants were no more effective than placebo at post-treatment: gambling symptom severity (SMD -0.32, 95% CI -0.74 to 0.09, n = 225), gambling expenditure (SMD -0.27, 95% CI -0.60 to 0.06, n = 144), depressive symptoms (SMD -0.19, 95% CI -0.60 to 0.23, n = 90), functional impairment (SMD -0.15, 95% CI -0.53 to 0.22, n = 110), and responder status (RR 1.24, 95% CI 0.93 to 1.66, n = 268). Opioid antagonists: Four studies (n = 562) evaluated opioid antagonists, with very low to low certainty evidence showing a medium beneficial effect of treatment on gambling symptom severity relative to placebo at post-treatment (SMD -0.46, 95% CI -0.74 to -0.19, n = 259), but no difference between groups in responder status (RR 1.65, 95% CI 0.86 to 3.14, n = 562). Mood stabilisers: Two studies (n = 71) evaluated mood stabilisers (including anticonvulsants), with very low certainty evidence suggesting that mood stabilisers were no more effective than placebo at post-treatment: gambling symptom severity (SMD -0.92, 95% CI -2.24 to 0.39, n = 71), depressive symptoms (SMD -0.15, 95% CI -1.14 to 0.83, n = 71), and anxiety symptoms (SMD -0.17, 95% CI -0.64 to 0.30, n = 71). Atypical antipsychotics:Two studies (n = 63) evaluated the atypical antipsychotic olanzapine, with very low certainty evidence showing a medium beneficial effect of treatment on gambling symptom severity relative to placebo at post-treatment (SMD -0.59, 95% CI -1.10 to -0.08, n = 63). Comparative effectiveness: Two studies (n = 62) compared antidepressants with opioid antagonists, with very low certainty evidence indicating that antidepressants were no more effective than opioid antagonists on depressive symptoms (SMD 0.22, 95% CI -0.29 to 0.72, n = 62) or anxiety symptoms (SMD 0.21, 95% CI -0.29 to 0.72, n = 62) at post-treatment. Two studies (n = 58) compared antidepressants with mood stabilisers (including anticonvulsants), with very low certainty evidence indicating that antidepressants were no more effective than mood stabilisers on depressive symptoms (SMD 0.02, 95% CI -0.53 to 0.56, n = 58) or anxiety symptoms (SMD 0.16, 95% CI -0.39 to 0.70, n = 58) at post-treatment. Tolerability and adverse events: Several common adverse effects were reported by participants receiving antidepressants (e.g. headaches, nausea, diarrhoea/gastrointestinal issues) and opioid antagonists (e.g. nausea, dry mouth, constipation). There was little consistency in the types of adverse effects experienced by participants receiving mood stabilisers (e.g. tiredness, headaches, concentration difficulties) or atypical antipsychotics (e.g. pneumonia, sedation, increased hypomania). Discontinuation of treatment due to these adverse events was highest for opioid antagonists (10% to 32%), followed by antidepressants (4% to 31%), atypical antipsychotics (14%), and mood stabilisers (13%). AUTHORS' CONCLUSIONS: This review provides preliminary support for the use of opioid antagonists (naltrexone, nalmefene) and atypical antipsychotics (olanzapine) to produce short-term improvements in gambling symptom severity, although a lack of available evidence precludes a conclusion regarding the degree to which these pharmacological agents can improve other gambling or psychological functioning indices. In contrast, the findings are inconclusive with regard to the effects of mood stabilisers (including anticonvulsants) in the treatment of disordered or problem gambling, and there is limited evidence to support the efficacy of antidepressants. However, these conclusions are based on very low to low certainty evidence characterised by a small number of included studies, high risk of bias, modest pooled sample sizes, imprecise estimates, moderate between-study heterogeneity, and exclusion of participants with psychiatric comorbidities. Moreover, there were insufficient studies to conduct meta-analyses on many outcome measures; to compare efficacy across and within major categories of interventions; to explore dosage effects; or to examine effects beyond post-treatment. These limitations suggest that, despite recommendations related to the administration of opioid antagonists in the treatment of disordered or problem gambling, pharmacological interventions should be administered with caution and with careful consideration of patient needs. A larger and more methodologically rigorous evidence base with longer-term evaluation periods is required before definitive conclusions can be drawn about the effectiveness and durability of pharmacological treatments for disordered or problem gambling.

[Gambling addiction as a side effect of low dose pramipexole in the treatment of restless legs syndrome].

Pathologic gambling is a rare but severe side effect of dopamine agonists (DA). Low dosage DA, as given when treating restless legs syndrome (RLS), has been thought only to have mild side effects. This case report describes two patients with low dosage pramipexole for RLS, who developed gambling addiction for a decade, highly affecting their quality of life. After stopping the treatment, the patients' gambling addiction ceased. Even though this is a very rare side effect, patients prescribed a DA should be informed of the risk of gambling addiction, independently of dosage.

Noradrenergic contributions to cue-driven risk-taking and impulsivity.

RATIONALE: The flashing lights and sounds of modern casinos are alluring and may contribute to the addictive nature of gambling. Such cues can have a profound impact on the noradrenaline (NA) system, which could therefore be a viable therapeutic target for gambling disorder (GD). While there is substantial evidence to support the involvement of NA in the impulsive symptoms of GD, its function in mediating the "pro-addictive" impact of cues is less understood. OBJECTIVE: We wished to investigate the role of NA in our rodent assay of decision making and impulsivity, the cued rat gambling task (crGT). Given that sex differences are prominent in addiction disorders, and increasingly reported in the monoaminergic regulation of behaviour, we also prioritised evaluating noradrenergic drugs in both sexes. METHODS: Female and male rats were trained to stability on the crGT and then given intraperitoneal injections of the noradrenaline reuptake inhibitor atomoxetine, the α2A receptor agonist guanfacine, the beta receptor antagonist propranolol, and the α2 receptor antagonist yohimbine. RESULTS: Atomoxetine dose-dependently improved decision-making score. Guanfacine selectively enhanced decision making in risk-preferring males and optimal performing females. Propranolol and yohimbine did not influence decision making. Atomoxetine and guanfacine reduced premature responses, while yohimbine bi-phasically affected this index of motor impulsivity. CONCLUSIONS: These results support the hypothesis that NA is an important neuromodulator of the cue-induced deficits in decision making observed in laboratory-based gambling paradigms, and suggest that NAergic drugs like atomoxetine and guanfacine may be useful in treating GD.

Current pharmacotherapy for gambling disorder: a systematic review.

Introduction: Gambling disorder is classified as an addictive disorder and is associated with significant distress and impairment in personal, social, occupational or other important areas of functioning. Although no pharmacotherapy has a formal indication for gambling disorder, data suggest potential benefits of specific medications.Area covered: This systematic review evaluated findings from 19 randomized controlled trials testing pharmacotherapies for the treatment of gambling disorder.Expert opinion: Few randomized controlled trials have studied pharmacotherapies for gambling disorder. Though results are limited, opioid antagonists like naltrexone showed promise in the pharmacological treatment of gambling disorder. Pharmacotherapy combined with psychotherapy treatments for gambling disorder may provide better rates of patient retention in comparison to pharmacology-only treatments, though further research is needed in this area. Future studies should address gaps relating to considerations of racial, ethnic, gender and other individual differences in clinical studies. Because gambling disorder often co-occurs with other psychiatric disorders, additional research is needed to test treatments for dually diagnosed patients.

Cold pressor pain and gambling disorder: implications for the opioid system.

OBJECTIVE: Gambling disorder (GD) is a common, disabling condition that often is exacerbated by stressful life events. Under stress, the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis are activated. The question, therefore, arises as to whether an abnormal sympathetic response can be found in individuals with GD. METHOD: Adult individuals with GD and no current co-occurring mental disorders were enrolled. Participants completed impulsivity and gambling-related questionnaires and underwent cold pressor evaluation. GD participants were compared with controls on measures of heart rate, blood pressure, and pain. RESULTS: Fifteen people with GD and 18 controls completed the study. Kaplan-Meier analysis indicated that the GD group withdrew their hand from the painful stimulus more rapidly than controls (Wilcoxon chi-square = 3.87, p = 0.049), suggestive of lesser pain tolerance. Subjective pain ratings and cardiovascular measurements did not significantly differ between groups. CONCLUSIONS: Individuals with GD manifested a relative intolerance to pain on the cold pressor paradigm, even though they physiologically did not seem to experience greater pain. Given the role of the opioid system in pain processing, it would be valuable in future work to examine whether cold pressor measures can predict response to treatments in GD, including with opioid antagonists.

Gambling and substance use: Comorbidity and treatment implications.

Gambling disorder is a common condition that was previously listed as an impulse control disorder, but is now considered a substance-related and addictive disorder. Gambling disorder has been associated with various untoward long-term outcomes including impaired quality of life, relationship break-ups, debt and mortgage foreclosure, and elevated risk of suicidality. This paper provides a concise primer on gambling disorder, with a special focus on its parallels with substance use disorders. We consider clinical presentations, comorbid expression, heritability, and treatment approaches (psychological and pharmacological). Lastly, we highlight new treatment directions suggested by the literature.

Treating gambling disorder with as needed administration of intranasal naloxone: a pilot study to evaluate acceptability, feasibility and outcomes.

BACKGROUND AND AIM: There is growing interest in the use of medication-assisted treatments for gambling disorder (GD). Opioid receptor antagonists are hypothesised to blunt the craving associated with gambling. This study was designed to assess the feasibility of using an intranasal naloxone spray to treat GD. DESIGN: An 8-week, open-label, uncontrolled pilot study. SETTING: A single study site in the capital region of Finland. SUBJECTS: Twenty problem gamblers (nine men) were randomised into two groups. Group A (n=10) took one dose into one nostril (2 mg naloxone), as needed, with a maximum of 4 doses/day (max. 8 mg/day). Group B (n=10) took one dose into each nostril (4 mg naloxone) as needed, with a maximum of 4 doses/day (max. 16 mg/day). INTERVENTION: Naloxone hydrochloride nasal spray. MEASURES: Acceptability and feasibility of the intervention were assessed. Use of study medication, adverse events, gambling frequency and gambling expenditure were recorded in a mobile diary. Problem gambling: South Oaks Gambling Screen (SOGS), depressive symptoms: Beck Depression Inventory (BDI) and alcohol use: Alcohol Use Disorders Identification Test were recorded. RESULTS: Study completion rate was 90%. Acceptability and feasibility scores were high. Group B used intranasal naloxone more frequently than group A, and consequently used more naloxone. No serious adverse events were reported. The postintervention SOGS scores were lower (median=4 (IQR=3.75) versus preintervention scores (median=12 (IQR=4.75)). Depressive symptoms were reduced during the trial (preintervention BDI median=9, IQR=9 vs postintervention BDI median=6, IQR=6). CONCLUSIONS: The acceptability and feasibility of using intranasal naloxone were high, and no serious adverse events were reported. Preliminary results suggest mixed results in terms of gambling behaviour (ie, reduced frequency but not expenditure) and decreased depressive symptoms. TRIAL REGISTRATION NUMBER: EudraCT2016-001828-56.

Impulsivity moderates the effects of dopamine D2 and mixed D1-D2 antagonists in individuals with gambling disorder.

BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.

Can Slot-Machine Reward Schedules Induce Gambling Addiction in Rats?

Similar to drugs of abuse, random-ratio reward schedules are highly motivating and, in humans, are thought to foster gambling addiction. Animal gambling models, however, have not yet demonstrated the compulsivity so characteristic of drug addiction. Three criteria have been used to evaluate addiction-like behavior in drug models: (1) response inhibition when reward is not available, (2) persistence under a progressive ratio schedule, in which the response-to-reward ratio is stretched, and (3) persistence in spite of punishment. We tested whether prolonged exposure (6 weeks) to a gambling-like reward schedule would induce addiction-like symptoms in rats. In two studies, separate groups were trained to respond to either random- or fixed-ratio schedules for food reward. We found that rats trained on random-ratio schedules showed higher response rates and dramatically shorter pauses after rewards. Tests of addiction-like behavior, however, were largely negative. Response rates were not different during cued no-reward periods nor when reward was coupled with punishment. We also found no group differences when food was devalued nor in reinstatement of reward-seeking after a 1-week delay. The sole exception to this pattern was that rats in the second experiment showed greater persistence on a progressive ratio test. After experiment two, subjects were also orally administered pramipexole, which caused increased perseveration during progressive ratio testing, especially in the random ratio group. While, it is possible that longer training or more appetitive rewards might have led to addiction-like behavior, our results, on the surface, suggest that random-ratio schedules are motivating but not addictive.

Efficacy of Pharmacological Interventions in Targeting Decision-Making Impairments across Substance and Behavioral Addictions.

Decision-making impairments reflect tendencies towards risky or unwise choices as manifested by presence of psychiatric symptoms or cognitive impairment (e.g. representation of value, inhibitory control-response selection, learning). Such impairments are suggested by the hallmark symptoms of substance and behavioral addictions, which include escalation over time (of substance intake or a given behavior), lack of control, neglect of other domains of life, and cognitive distortions (such as 'chasing losses' in gambling disorder). Amongst the putative behavioral addictions, most epidemiological data exist for gambling disorder, which is now included in DSM-5 as a substance-related and addictive disorder. However, other disorders share parallels and may also constitute behavioral addictions, such as compulsive stealing (kleptomania), compulsive shopping, and compulsive sexual behavior. The current paper presents a narrative review of evidence for cognitive decision-making impairments in addictions, as well as pharmacological treatments of these disorders that may have relevance for improving decision-making. We find that objective decision-making deficits have been widely reported in patients with substance use disorders and gambling disorder, compared to controls. Decision-making in the other behavioral addictions is under-studied. Evidence-based pharmacological treatments for some of these addictive disorders, for example, opioid antagonists and glutamatergic agents, modulate neural systems playing key roles in decision-making. But clinical trials have seldom examined effects of such treatments on objective decision-making measures. Future research directions are discussed, including the need to include standardized outcome measures of decision-making (tasks and imaging) alongside traditional clinical measures, to better understand and enhance underlying treatment mechanisms.

The ß-adrenoceptor blocker propranolol ameliorates compulsive-like gambling behaviour in a rodent slot machine task: implications for iatrogenic gambling disorder.

Previous work has shown that chronic administration of the dopamine D2/3 receptor agonist ropinirole invigorates performance on a rodent slot machine task (rSMT). This behavioural change appears superficially similar to the iatrogenic gambling disorder (GD) observed in a sub-set of patients with Parkinson's disease (PD), and has been associated with increased activation of the intra-cellular signalling proteins GSK3ß and CREB in the striatum. Here, we wanted to determine whether this response to ropinirole could be attenuated by targeting these signalling proteins, and if the loss of dopaminergic innervation characteristic of PD would alter ropinirole's effects on the rSMT. Male Long Evans rats were trained on the rSMT. Dopaminergic terminals innervating the dorsolateral striatum were then lesioned bilaterally using the neurotoxin 6-hydroxydopamine hydrochloride (6-OHDA). Subsequently animals were implanted with osmotic mini-pumps delivering ropinirole. Lastly, animals were given dietary lithium (Li+ ), to inhibit the activation of GSK3ß, or injections of the ß-adrenoceptor antagonist propranolol, which potently inhibits CREB as a secondary mechanism of action, and any changes in ropinirole-induced increases in compulsive-like engagement in the rSMT evaluated. Chronic ropinirole increased the number of trials animals completed, reproducing our original finding. This increase in task engagement was not altered in animals with 6-OHDA lesions, a putative model of early PD. In addition, the effects of ropinirole were not attenuated by administration of Li+ , but were ameliorated by propranolol. These data suggest that propranolol may represent a potential pharmacotherapy for the treatment of iatrogenic gambling.

Pharmacological Treatments for Disordered Gambling: A Meta-analysis.

Disordered gambling is a public health concern associated with detrimental consequences for affected individuals and social costs. Currently, opioid antagonists are considered the first-line treatments to reduce symptoms of uncontrolled gambling. Only recently, glutamatergic agents and combined pharmacological and psychological treatments have been examined appearing promising options for the management of gambling disorder. A multilevel literature search yielded 34 studies including open-label and placebo-controlled trials totaling 1340 participants to provide a comprehensive evaluation of the short- and long-term efficacies of pharmacological and combined treatments. Pharmacological treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss (Hedges's g: 1.35, 1.22, 0.80, respectively). The controlled effect sizes for the outcome variables were significantly smaller (Hedges's g: 0.41, 0.11, 0.22), but robust for the reduction of global severity at short-term. In general, medication classes yielded comparable effect sizes independent of predictors of treatment outcome. Of the placebo controlled studies, results showed that opioid antagonists and mood stabilizers, particularly the glutamatergic agent topiramate combined with a cognitive intervention and lithium for gamblers with bipolar disorders demonstrated promising results. However, more rigorously designed, large-scale randomized controlled trials with extended placebo lead-in periods are necessary. Moreover, future studies need to monitor concurrent psychosocial treatments, the type of comorbidity, use equivalent measurement tools, include outcome variables according to the Banff, Alberta Consensus, and provide follow-up data in order to broaden the knowledge about the efficacy of pharmacological treatments for this disabling condition.

The use of naltrexone in pathological and problem gambling: A UK case series.

BACKGROUND AND AIMS: To investigate the potential indications and adverse effects of using the opioid antagonist naltrexone to treat problem gamblers. CASE PRESENTATION: The files of the 1,192 patients who were referred to the National Problem Gambling Clinic between January 2015 and June 2016 were audited. Seventeen patients were considered appropriate for treatment with naltrexone, having attended and failed to respond to psychological therapies at the clinic. Fourteen patients were placed on a regimen of 50 mg/day naltrexone. DISCUSSION: Of the 14 patients who were treated with naltrexone, there were 10 for whom sufficient follow-up existed to analyze the treatment efficacy and side effects of naltrexone. Patients showed significant decreases in their craving to gamble and the majority (60%) were able to abstain completely from gambling in the treatment period, with a further 20% reducing their gambling to almost nothing. The reported side effects from the naltrexone included: loss of appetite, gastrointestinal pain, headaches, sedation, dizziness, and vivid dreams. Two patients with concurrent alcohol-use disorder relapsed during the treatment. One patient relapsed after the treatment period. CONCLUSIONS: The study showed significant outcomes in reducing gambling cravings for the sample set. Given the design of the study as a case series, there was no control group, and a number of patients were on other psychotropic medications. We recommend care when prescribing to those suffering from concurrent alcohol-use disorder.

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

Opioid Antagonists for Pharmacological Treatment of Gambling Disorder: Are they Relevant?

BACKGROUND: To date, no drugs have been approved for gambling disorder. Numerous publications have described the value of opioid antagonists. Indeed, the mesocorticolimbic dopaminergic pathway has been suggested as the underlying cause of reward-seeking behaviour, and it is modulated by the opioid system. OBJECTIVE: This study aims to evaluate the relevance of opioid antagonists for treating GD. METHOD: A systematic literature review was conducted. A search of the PubMed electronic database, PsycINFO and the Cochrane Systematic Review Database without any limits was performed. RESULTS: There is little information concerning the effects of opioid antagonists on GD. The total search with "nalmefene and gambling" without any limits revealed only 11 articles. The search with "naltrexone and gambling" without any limits generated 47 articles. Nevertheless, the best available data support the use of opioid antagonists, particularly in individuals with a history of alcohol use disorder or strong gambling urges. CONCLUSION: Future trials are still needed. Indeed, opioid antagonists effectiveness has been investigated in only a limited number of patients, clinical trials do not reflect the heterogeneity of GD and there is little knowledge of the predictive factors of response to treatments. Moreover, differential affinity to nalmefene for kappa receptors may be associated with a particular effect in a yet to be defined addiction phenotype. Head to head comparisons between naltrexone and nalmefene would be helpful in combining other medication or psychotherapy. The identification of subgroups of patients that are more likely to benefit from opioid antagonists should be a goal.