Tulburările de joc patologic în ICD-11 – un review al mecanismelor neurobiologice care stau la baza includerii lor în adicţiile comportamentale

In the new ICD-11, gambling disorder is characterized by a pattern of persistent or recurrent gambling behavior, which may be online (i.e., over the internet) or offline, manifested by: 1) impaired control over gambling (e.g., onset, frequency, intensity, duration, termination, context); 2) increasing priority given to gambling to the extent that gambling takes precedence over other life interests and daily activities; and 3) continuation or escalation of gambling despite the occurrence of negative consequences. The behavior pattern is of sufficient severity to result in significant impairment in personal, family, social, educational, occupational or other important areas of functioning. The pattern of gambling behavior may be continuous or episodic and recurrent. The gambling behavior and other features are normally evident over a period of at least 12 months in order for a diagnosis to be assigned, although the required duration may be shortened if all diagnostic requirements are met and symptoms are severe⁽¹⁾.

In 2013, in DSM-5, gambling disorder has been moved to substance-related and addictive disorders, owing to its phenomenological, neurobiological, genetic, and treatment-related similarities with substance use disorders⁽²⁾. Charles O’Brien, chair of the workgroup for substance-related disorders in DSM-5, remarked that neuroimaging and neurochemical studies have made “a strong case that gambling activates the reward system in much the same way that a drug does”⁽³⁾. Therefore, untill 2013, the consensus was for moving the pathological gambling from impulse control disorder to addictive disorder and not to include the problematic internet use as a diagnostic entity. On the consequence, the reclassification of gambling disorder under addictive disorders section in ICD-11 has been done after a thorough debate, as the overwhelming evidence for the reclassification is too convincing to be ignored by World Health Organization⁽⁴⁾.

In gambling disorder, impulsive-choice behavior has been studied using decision-making tasks, as well as tasks measuring the discounting of rewards by probability and delay using the Cambridge Gambling Task. In a study⁽⁵⁾, the participants suffering from either gambling disorder, or alcohol addiction did not differ significantly in their rational choices compared to controls. Anyhow, subjects suffering from either alcohol addiction, or gambling disorder presented elevated risk-taking, and those with alcohol addiction also being slower decision-makers compared to control and gambling disorder participants.

Comparing impulsivity problem and gambling disorder, another study⁽⁶⁾ found an abnormal impulsive choice-making in both groups, while only the group with gambling disorder revealed greater action impulsivity.

Several neuroimaging studies have focus on the neural correlation of impulsive choice and action behavior using a variety of tasks^(7,8), highlighting that patients were slower than healthy control subjects, although equally as accurate. Moreover, craving has been shown to affect impulsive choices: altered activity in the midbrain and striatum was observed during the making of impulsive choices in high-craving trials⁽⁹⁾.

As for the compulsivity, it looks to be less well-investigated than impulsivity. Anyhow, the relationship between impulsivity and compulsivity is still a matter of debate; compulsivity can be characterized by perseverative, repetitive actions that are excessive and inappropriate in a given situation⁽¹⁰⁾.

Habit formation is considered to have a crucial role in drug addiction, as initially impulsive drug-seeking may become compulsive with continued use. Much evidence from both human and animal studies suggests that the dorsal part of the striatum plays a role in both habitual responding and in initiating automatic stimulus-response tendencies⁽¹⁰⁾.

It remains the dilemma whether compulsive tendencies constitute a risk factor for addiction or they occur as a consequence of prolonged drug use, or whether both hold true. Either way, the relationship between compulsivity and addiction is thought to be influenced by specific facets of compulsivity and types and patterns of substance use⁽¹²⁾.

Although gambling disorder is characterized by compulsivity-related behaviors, such as loss chasing and lucky rituals, relatively few studies have systematically examined compulsivity in gambling disorder. Nevertheless, it is important to note that the reduced cognitive flexibility observed in gambling disorder has recently been suggested to be more likely the result of aberrant reward-based learning, rather than a general problem with cognitive flexibility⁽¹³⁾.

According to cue-reactivity studies, dependent patients show increased brain activity in response to visual drug-related cues in parts of the mesocorticolimbic dopamine system, the medial prefrontal cortices, the visuo-spatial attention network (fronto-occipito-parietal regions) and the temporal lobe, compared to non-addicted individuals. Studies also show that responses to alcohol-related cues can also comprise behaviors such as increased craving intensity and a higher subsequent relapse risk⁽¹⁴⁾. Neuroimaging studies have revealed diminished brain response to non-drug-related cues in drug-addicted groups⁽¹⁵⁾. Combining these data, researchers have argued that “SADs” are characterized by an increased sensitivity to drug rewards and a reduced response to non-drug rewards, that favorize certain vulnerable individuals to actively search for drugs in preference over more socially acceptable goals⁽¹⁶⁾.

From a diagnostic perspective, the criteria for gambling disorder (as proposed for ICD-11) overlap considerably with those for substance abuse/dependence; i.e., preoccupation with the behavior in question, diminished control over behavioral engagement and adverse psychosocial consequences related to behavior. Now, we understand that gambling is a pleasurable leisure activity for many people, whereas most other behaviors that are the focus of “ICDs” are not (e.g., stealing, fire-setting)⁽³⁾. In DSM-5, the “ICD” category is now also characterized by behaviors that violate the rights of others or bring an individual into conflict with social norms or authority figures. As we realize that compulsive acts are mental acts performed with the purpose of reducing anxiety or distress (“negative reinforcement”), instead gambling produces a “positive reinforcement” for controlled and addicted gamblers individuals alike. In the end, after a period of repeting the act, the behavior may become more compulsive and might not be accompanied by pleasurable, hedonic emotions or conducted for the sake of pleasure⁽¹⁶⁾.

Newer research indicates augmented choice impulsivity among patients suffering from “SADs” and gambling disorder. Compulsive behavior contributes to “SADs” and gambling disorder, and may become increasingly more significant with the progression of each disease⁽¹⁷⁾.

An alteration in reward processing determined  by functional and structural changes in the meso-corticolimbic reward system, alike those that appear in “SADs”, is a hallmark of gambling disorder. An increased salience of stimuli linked to problematic behavior is a unique feature of “SADs” and gambling disorder. So far, this has not been studied in patients suffering from “ICDs” like kleptomania or pyromania⁽¹⁸⁾.

Regarding reward anticipation, it seems it is dysfunctional irrespective of the type of reward, be it drugs or gambling. These findings suggest that dopaminergic dysfunction during reward anticipation could represent a trait of both substance-related and behavioral addictions, although it requires further study.

As impaired impulse control and VMPFC dysfunction are also a hallmark of drug addiction, and it is difficult to see why gambling disorder should remain placed in the “ICD” category because of this finding⁽¹⁹⁾.

It has been noticed in the theory of neurotransmitters the imbalances between the neurotransmitters, based on studies of gambling disorder and/or other disorders; noradrenaline was hypothesized in the ICD for relevant aspects of excitement, serotonin in initiation and cessation of behavior, dopamine to reward and enhance behavior, and opioids for pleasure or excitement⁽²⁰⁾.

Gambling behavior was associated with autonomous excitement during blackjack gambling, each link having augmented in heart rate and increases in noradrenergic measures^(21,22).

During blackjack games, heart rate and noradrenergic rhythm become higher in men with gambling problems compared to those without such issues^(21,22).

Beside a potential role in excitement, norepinephrine may be linked to other aspects of gambling disorder. For example, the activity of noradrenergic influences the function of the prefrontal cortex and networks of attention back, and drugs (for example, transport inhibitor of norepinephrine atomoxetine and agonists, alpha-2 adrenergic agonist clonidine and guanfacine) acting via mechanisms blockers have been shown to be effective in the treatment of attention deficit disorders – ADHD⁽²³⁾. It has been proved that adrenergic drugs influence specific aspects of impulse control in animal and human studies⁽²⁴⁾. These findings suggest several possible roles for adrenergic function in the gambling disorder and its treatment, and additional investigations are needed in this area to examine these possibilities.

As for serotonin, its function has been considered to be of substantial importance in mediating impulse control. Individuals with a clinically impacted impulse control level, including those with gambling disorder⁽²⁵⁾, have shown low levels of the 5-hydroxy indoleacetic acid metabolite. People with gaming disorder or other disorders or with behaviors characterized by impulse control (e.g., impulsive aggression) have different behavioral and biochemical responses to serotoninergic drugs than healthy control subjects. People with gambling disorder reported a high level after the administration of meta-chlorophenylpiperazine (m-CPP), a partial serotonin agonist that binds to 5HT1 and 5HT2 receptors with a high affinity for the 5HT2c receptor⁽²⁶⁾.  

This response was in contrast to that of subjects in the control group and was similar to high evaluations previously reported by antisocial, frontal and alcoholic subjects after receiving the drug. The prolactin response to m-CPP also distinguished gambling disorder and control groups, with a higher increase observed in the gambling disorder  group.

Serotoninergic bands have been used together with brain imaging in people with unpredictable impulse control. In patients with impulsive aggression compared to the non-existent, a blunt response in the ventromedial prefrontal cortex (vmPFC) was observed in response to m-CPP⁽²⁷⁾ or the indirect agglutinant fenfluramine. Similar studies have not been conducted so far in the gambling disorders, although other investigations involved the vmPFC function in the gambling disorder.   

Consecutively, the facts suggested an important role for serotonin function in gambling disorder  and impulse control, and serotonergic drugs have been investigated in the treatment of gambling disorder⁽²⁸⁾. Serotonin receptor inhibitors show mixed results. In a small, placebo-controlled, double-blind, crossover fluvoxamine, active and placebo arms were significantly distinct during the second half of the study, the active drug being superior to placebo⁽²⁹⁾.

These studies have excluded people with psychiatric disorders that occur simultaneously. An open-label study of escitalopram, followed by double-blind discontinuation, was performed in patients with gambling disorder and associated anxiety disorders⁽³⁰⁾. During the open phase, measurements of gambling behavior and anxiety have been improved in parallel. Randomization to placebo was associated with the resumption of measurements of gambling and anxiety behaviors, while randomization for the active drug was associated with sustained responses. Although preliminary, all these data suggest that there are significant individual differences between people with gambling disorder, and that these differences have important implications for response to treatment.

Another important neurotransmitter, dopamine, is involved in rewarding and reinforcing gambling and drug addiction behaviors⁽³¹⁾. However, few studies have directly investigated the role of dopamine in gambling disorder. Variable observations have been reported for measuring the cerebrospinal fluid of dopamine and its metabolites in gambling disorder^(32,33). Gambling disorders’ initial molecular genetic studies often included methodological limitations, such as the lack of stratification on race or ethnicity, incomplete diagnostic assessments, and subsequent studies used race/ethnic control methods. In the DSM-4 diagnosis they did not have differences in the frequencies of TaqA1 alleles which were observed in gambling disorder cases⁽³³⁾.

Gambling disorders have been observed in people with Parkinson’s disease (PD), a disorder characterized by the degeneration of dopamine and other systems⁽³⁴⁾. PD patients are treated with drugs that promote dopamine function (e.g., levodopa or dopamine agonists, such as pramipexole or ropinirole) or interventions (e.g., deep brain stimulation) that promote neurotransmission by related circuits^(34,35).

Parkinson’s disease subjects with and without gambling disorder have differentiated by different impulsivity, searching for the new, personal alcoholism or within the family⁽³⁵⁾. The possible impact of these and other variables of individual difference requires further studies in investigations on pathophysiology and treatment for DCI in gambling disorders.

There are patients who cannot tolerate higher doses of levodopa used in order to control gambling disorder symptoms, while others may abuse these medications⁽³⁶⁾. Together, these findings indicate that more research is needed in the pathophysiology and treatments for DCI in the gambling disorder^(37,38).    

On the other hand, glutamate, the most abundant excitatory neurotransmitter, has been involved in motivational processes and drug addiction⁽³⁹⁾. Based on the data and on preliminary findings suggesting a role for glutamatergic neurotransmission, the glutamatergic modulator N-acetylcysteine was also investigated in the gambling disorder treatment⁽⁴⁰⁾.

The design study included open treatment, followed by double-blind discontinuation. During the open phase, gambling symptoms improved significantly. After double-blind discontinuation, the improvement was maintained in 83% of respondents randomized to active drugs, compared with 29% of those randomized to placebo. These promising data suggest the necessity for deeper investigations on glutamatergic contributions to gambling disorder therapies⁽⁴⁰⁾.

Opioids have been involved in pleasant and satisfying processes, and opioid function can influence neurotransmission in the mesolimbic pathway that extends from the ventral tegmental area to the accumbens nucleus or ventral striatum⁽⁴¹⁾. Based on the resemblance between gambling disorder and dependencies, such as alcohol dependence, opioid antagonists have been evaluated in gambling disorder treatment.

Randomized, placebo-controlled, double-blind studies evaluated the efficacy and tolerability of naltrexone and nalmefene. Larger doses of naltrexone (mean study final dose =188 mg d-1, range up to 250 mg d-1) were superior to placebo in the treatment of gambling disorder⁽⁴²⁾. As with alcohol dependence, the drug has been particularly useful for people with heavy gambling difficulties at the onset of treatment. However, liver function test abnormalities were observed in over 20% of subjects receiving an active drug during the short study. Nalmefen, an opioid antagonist that is not associated with impaired hepatic function, was subsequently evaluated⁽⁴³⁾.

Nalmefene was superior to placebo, and abnormal liver function test abnormalities were not observed. The dose with the highest efficacy and tolerability was the 25 mg d-1 dose, which is approximately equivalent to the 50 mg d-1 dose commonly used in the treatment of alcohol or opiate dependence. Another analysis of the outcome of treatment in patients receiving opioid antagonists identified a family history of alcoholism, most strongly associated with a positive drug response, a conclusion consistent with the literature on alcoholism^(43,44).

The extent to which interference of other factors linked with the outcome to treatment of opioid antagonists in alcoholism (e.g., allelic variants of the gene encoding the opioid receptor)⁽⁴⁵⁾ in relationship to gambling disorder treatment requires further studies.

In synthesis, we believe that the new section of behavior addictions in ICD-11 represents a breakout point in the field of addiction research, the neuropsychological research being augmented by neuroimaging techniques in an outstanding international scientific joint venture that will gather more relevant data in the next years, using the first ever and biggest medical electronic database.