Current Psychiatry Reviews, 2012, 8, 20-24
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The Neuropsychopharmacology of Pathological Gambling Kourosh Zakeri1 and Marc N. Potenza*,1,2 Departments of Psychiatry1, Neurobiology2, and Child Study Center2, Yale University School of Medicine, USA Abstract: Pathological gambling (PG) is an impulse control disorder with prevalence estimates in the range of 0.2-2% in the general population. PG can significantly impact one’s ability to function as it may negatively influence social, financial, and occupational aspects of life. Historically, PG has received relatively little attention from researchers and clinicians, and few treatments, particularly pharmacological, have been both validated and widely employed. Given the clinical relevance of PG, it is important that researchers examine pharmacological and behavioral treatments for their safety and efficacy and that clinicians use empirically validated therapies. Multiple neurochemicals, including serotonin, dopamine, norepinephrine, and opioids, and related neurocircuitry, particularly ventral cortico-striatal pathways, have been implicated in PG. The neurobiological rationale for therapies, particularly pharmacological ones, is reviewed with a perspective on the generation of improved prevention and treatment strategies for PG.
Keywords; Addiction, Functional magnetic resonance imaging, Gambling, Impulse control disorder PATHOLOGICAL GAMBLING Gambling can be defined as the act of putting a possession of value at risk in an attempt to gain something of greater value [1]. Historically, excessive gambling has been considered a bad habit or irresponsible behavior. It was not until 1980 [2] that clinicians defined criteria for excessive gambling, termed pathological gambling (PG), in the Diagnostic and Statistical Manual (DSM). Classified as an 'impulse control disorder (ICD) not elsewhere categorized,' estimates of PG prevalence typically range from 0.2-2%, with lower estimates typically found when employing strict diagnostic thresholds [3]. PG shares many core features with drug dependence (DD) and thus PG has been proposed to represent a non-substance or “behavioral” addiction [4, 5]. Proposed core components of addiction include (I) continued engagement in a behavior despite adverse consequences, (II) diminished self-control over engagement in the behavior, (III) compulsive engagement in the behavior, and (IV) an appetitive urge or craving state prior to the engagement in the behavior [5]. Similarities between PG and DD are reflected in the diagnostic criteria which include aspects of tolerance, withdrawal, interference in major areas of life functioning and repeated unsuccessful attempts to cut back or quit. These commonalities between PG and DD suggest that biological features of DD, and therapeutic strategies employed for DD, might be relevant to PG. Up until the past decade, there has been relatively little investigation into the biology and treatment of PG [6]. Early investigations have implicated multiple neurotransmitters, and specific roles for these in PG have been proposed based both on studies of individuals with PG and other available data. Specifically, norepinephrine has been proposed to *Address correspondence to this author at the Departments of Psychiatry1, Neurobiology2, and Child Study Center2, Yale, University School of Medicine, USA; E-mail: [email protected] 1875-6441/12 $58.00+.00
relate to arousal and excitement, serotonin to behavioral initiation and cessation, dopamine to rewarding and reinforcing aspects of behaviors, and opioids to pleasure and urges [7]. Data supporting the involvement of these neurotransmitters in PG are reviewed below. NEUROTRANSMITTERS Specific neurotransmitters have been hypothesized to play specific roles in PG and DD. Norepinephrine has been associated with excitement and arousal [8], dopamine with reward and reinforcing behaviors [9-11], and serotonin in behavioral initiation and cessation (or impulse control) [1215]. Additionally, opioids have been implicated in pleasure and urges [7]. These neurotransmitters may also play other roles, and other neurotransmitters (e.g., glutamate) may also contribute importantly. NOREPINEPHRINE Individuals with PG have been found to have high levels of norepinephrine and/or its metabolites both centrally and peripherally [16, 17], and levels have been found to correlate with measures of extraversion [18]. Noradrenergic measures have also been found to elevate during gambling or gambling-like behaviors (e.g., Pachinko play) in individuals with and without PG [19-21]. Given the link of norepinephrine with excitement and arousal it would be of value to investigate norepinephrine as a potential biomarker of excitability in PG in future studies. Additionally, drugs that target adrenergic regulation may have utility in the treatment of PG (see below), particularly for individuals with PG who may be extroverted and/or exhibit hyperarousal. SEROTONIN Serotonin has been linked to various forms of impulse dyscontrol, including PG. Individuals with disorders characterized by poor impulse control (alcoholism, PG, pyromania) have been found to have low levels of the serotonin metabo© 2012 Bentham Science Publishers
The Neuropsychopharmacology of Pathological Gambling
lite 5-hydroxyindoleacetic acid (5HIAA) [14, 22]. Individuals with poor impulse control, including those with PG, show different behavioral and biological responses to serotonergic drugs. For example, individuals with PG show a blunted prolactin response to clomipramine, a drug which blocks the serotonin and norepinephrine transporters [23]. Individuals with PG, like those with cluster B personality disorders or alcoholism, report a euphoric response or “high” following administration of the serotonergic drug metachlorophenylpiperazine (mCPP), a compound with partial agonist action at 5HT1 and 5HT2 receptors [12]. This behavioral response differs in control comparison subjects who typically report an aversive response. Individuals with PG also show an enhanced prolactin response to mCPP. In brain imaging studies, individuals with impaired impulse control (impulsive aggression or alcoholism) have demonstrated in response to challenges with pro-serotonergic drugs (fenfluramine, meta-chlorophenylpiperazine (m-CPP)) blunted activation of the ventromedial prefrontal cortex (vmPFC), a region implicated in decision-making and impulse control, including in ICDs like PG (see ”Functional Imaging”) [2426]. Given the biological and behavioral responses to serotonergic agents and pre-clinical data implicating serotonin in impulse control, further investigation of the complex serotonin system is warranted in PG. For instance, levels of serotonin 1B receptor in the ventral striatum have been associated with problem gambling severity in PG, suggesting that this receptor may in part contribute to differences in ventral striatal activity observed in PG [27]. DOPAMINE Low cerebrospinal fluid (CSF) levels of dopamine and higher levels of its metabolites have been found in subjects with PG as compared to those without [17], although these findings may not persist when controlling for CSF flow rates [22, 28]. High peripheral levels of dopamine have been observed in problem gamblers while engaging in casino gambling [21]. The pro-dopaminergic drug amphetamine has been found to prime gambling-associated motivations and responses in individuals with PG [29]. An investigation from the same laboratory found that the D2-like dopamine receptor antagonist haloperidol also facilitated gambling-related motivations and responses [30], suggesting that the effects of amphetamine on gambling behaviors might involve other (e.g., D1-like) dopaminergic mechanisms or ones related to other influences (e.g., on noradrenergic systems). Alternatively, individual differences (e.g., related to impulsivity) may influence responses to dopaminergic drugs in PG, as has been suggested in preliminary studies with modafinil [31]. A role for dopamine in ICDs in individuals with Parkinson’s disease (PD) has been investigated [32-34]. ICDs, including PG, have been associated with dopamine agonist use, younger age, earlier age of PD onset, ICDs prior to PD onset, measures of novelty seeking and impulsivity, and personal or family histories of alcoholism [33, 34]. Administration of dopamine replacement therapies may influence aspects of decision-making and impulsivity differently in people with PD and ICDs as compared to those with PD alone [35, 36]. These findings may reflect difference in ventral striatal function, as has been observed in people with PD and PG as compared to those with PD alone [37].
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FUNCTIONAL IMAGING Brain imaging studies suggest that multiple neurocircuits are involved in the pathophysiology of PG. Central to PG, DD and other disorders characterized by impaired impulse control are motivational neural pathways. A central component of motivational neural pathways are cortico-striatothalamo-cortical circuits, with more ventral components particularly relevant to impulsive and reward-driven behaviors [38-40]. Consistently, one of the most frequently implicated brain regions is the vmPFC, and individuals with PG when compared to those without have been found to demonstrate less activation of this brain region when viewing gamblingrelated material [41], performing a test of cognitive control [42], engaging in simulated gambling [43], or performing a decision-making task [44]. These findings are similar to those observed in other groups characterized by impaired impulse control; e.g., the region displaying relatively diminished activation in the PG group in the cognitive control study was largely identical to the distinguishing individuals with and without bipolar disorder [45]. Another frequently implicated brain region in PG neuroimaging studies is the ventral striatum. Individuals with PG as compared to control subjects have demonstrated relatively diminished activation of the ventral striatum when performing simulated gambling or when viewing gambling tapes [43, 46]. Amongst individuals with Parkinson’s disease, those with PG as compared to those without PG showed at baseline relatively diminished raclopride binding (reflecting D2-like dopamine receptor availability) in the ventral striatum, and demonstrated greater raclopride displacement when performing a simulated gambling task, suggesting greater dopamine release during task performance [47]. GENETICS Twin studies have identified a significant heritable component to PG, with about half of the variance appearing genetic in nature for syndromal PG [48, 49]. Twin studies also suggest that genetic and environmental contributions to alcohol dependence and antisocial personality and conduct disorders overlap with those contributing to PG, whereas the co-occurrence between PG and major depression appears predominantly genetic in nature [50-52]. Specific allelic variants have been implicated, albeit inconsistently, in PG [53-57]. It would be of value to further investigate genetic influences in larger samples of individuals with PG (e.g., in genome-wide association studies). TREATMENT Although many individuals may recover without formal intervention [58], behavioral and pharmacological treatments have been shown to be beneficial and early intervention may result in diminished gambling-related problems and improved quality of life. BEHAVIORAL THERAPIES Multiple behavioral interventions and therapies have been investigated in PG [59-63]. Gamblers Anonymous (GA), a 12-step approach based on Alcoholics Anonymous, has been in existence since 1957 and is the most widely available intervention. Studies of its efficacy have been
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sparse, with data indicating that individuals typically attend only for one or two sessions. However, GA attendance in conjunction with formal treatment has been associated with better treatment outcome [64]. Structured behavioral therapies with empirical support include cognitive behavioral therapy (CBT), motivational interviewing, imaginal desensitization in conjunction with motivational interviewing, and brief interventions [63, 65]. The largest study performed to date involved 231 individuals with PG randomized to one of three conditions: therapistdelivered CBT plus GA, CBT manual without therapist delivery plus GA, and GA referral alone. Although all three groups reported diminished gambling over time, those receiving therapist-delivered CBT showed the greatest reductions [66]. PHARMACOLOGICAL THERAPIES Multiple classes of medications have been examined for their tolerability and efficacy in the treatment of PG. Given high frequencies of placebo response, data from placebocontrolled trials offer the best support for or against the efficacies of specific pharmacotherapies; thus, data from placebo-controlled blinded studies are described below. Some drugs (e.g., olanzapine, a drug that blocks dopamine and serotonin receptors and topiramate, a glutamatergic agent) have shown negative results in clinical trials [67-69]. Serotonin reuptake inhibitors have shown mixed results with respect to their efficacy in treating PG, and it is possible that these drugs may have particular benefit for individuals with PG and co-occurring affective conditions (e.g., anxiety disorders – reviewed in [63]). In a modestly sized, randomized, double-blind, placebo-controlled trial, the mood-stabilizing drug lithium was shown to be superior to placebo in the treatment of individuals with co-occurring PG and bipolar spectrum disorders with respect to symptom reductions in both gambling and manic domains [70]. Preliminary data suggest the efficacy of the glutamatergic agent N-acetyl cysteine in the treatment of PG, consistent with preliminary studies in cocaine dependence and nicotine dependence [71]. The most consistent data involve the use of opioid antagonists (naltrexone and nalmefene), which have been found to be superior to placebo in four randomized, double-blind, placebo-controlled trials [63], including the first multi-center pharmacotherapy study of PG, one that involved over 200 subjects. The drugs appear particularly effective for individuals with strong gambling urges and those with a family history of alcoholism [72], findings consistent with those from the alcohol research field. Together, these findings suggest that pharmacotherapy selection in the treatment of PG should be considered and guided by co-occurring symptomatology. Given the contributions of adrenergic and dopaminergic systems to aspects of impulse control, various studies have examined drugs acting on these systems in treatment studies in disorders characterized by impaired impulse control. Though adrenergic agents have not been systematically investigated in PG, given positive findings of adrenergic agents (e.g., atomoxetine, guanfacine) in the treatment of other disorders characterized by impaired impulse control, they warrant further examination in PG. The utility of dopa-
Zakeri and Potenza
minergic drugs might be more limited. On the one hand, dopamine agonists (e.g., pramipexole, ropinirole) have been associated with ICDs including PG in PD, and prodopaminergic drugs like amphetamines have been associated with pro-gambling thoughts and behaviors [29]. On the other hand, the D2-like dopamine receptor antagonist haloperidol has been linked to pro-gambling thoughts and behaviors [30], and a drug with D2-like dopamine receptor antagonistic properties (olanzapine) has not shown efficacy in controlled trials in the treatment of PG [67, 68]. Also, bupropion, a drug with dopaminergic properties, did not differ from placebo in the treatment of PG [73]. Data suggest that indirect modulation of mesolimbic function, through opioid antagonists or glutamatergic agents like n-acetyl cysteine, might be of greater benefit in the treatment of PG. Additional studies targeting other mesolimbic neurotransmitter systems (e.g., serotonin 1B receptors) also warrant consideration, as do drugs that target other relevant circuits (e.g., those involved in stress responsiveness, impulsivity and attention, to name several). CONCLUSION Recent studies into the neurobiology of PG have provided a rational basis for approaching treatment development in PG. Multiple behavioral and pharmacological treatments have shown preliminary efficacy, although larger studies involving more diverse groups of individuals followed for longer periods of time are warranted. As the neurobiological mechanisms of PG are better understood with respect to how they relate to individual differences amongst people with PG, clinicians will be in a better position to select appropriate therapies for specific individuals. DISCLOSURE All authors reported no conflict of interest in the content of this paper. Dr. Potenza has received financial support or compensation for the following: Dr. Potenza has consulted for and advised Boehringer Ingelheim; has financial interests in Somaxon; has received research support from the National Institutes of Health, Veteran’s Administration, Mohegan Sun Casino, the National Center for Responsible Gaming and its affiliated Institute for Research on Gambling Disorders, and Psyadon and Forest Laboratories pharmaceuticals; has participated in surveys, mailings or telephone consultations related to drug addiction, impulse control disorders or other health topics; has consulted for law offices on issues related to addictions or impulse control disorders; has provided clinical care in the Connecticut Department of Mental Health and Addiction Services Problem Gambling Services Program; has performed grant reviews for the National Institutes of Health and other agencies; has guest-edited journal sections; has given academic lectures in grand rounds, CME events and other clinical or scientific venues; and has generated books or book chapters for publishers of mental health texts. FUNDING This work was supported in part by the NIH (R01 DA019039, RL1 AA017539, RC1 DA028279), the VA VISN1 MIRECC, the Connecticut Department of Mental Health and Addiction Services, and a Center of Research
The Neuropsychopharmacology of Pathological Gambling
Excellence Award from the Institute for Research on Gambling Disorders. The content of the manuscript reflect the views and thoughts of the authors and not necessarily those of the funding agencies.
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Revised: August 22, 2011
Accepted: September 20, 2011
20
The Neuropsychopharmacology of Pathological Gambling Kourosh Zakeri1 and Marc N. Potenza*,1,2 Departments of Psychiatry1, Neurobiology2, and Child Study Center2, Yale University School of Medicine, USA Abstract: Pathological gambling (PG) is an impulse control disorder with prevalence estimates in the range of 0.2-2% in the general population. PG can significantly impact one’s ability to function as it may negatively influence social, financial, and occupational aspects of life. Historically, PG has received relatively little attention from researchers and clinicians, and few treatments, particularly pharmacological, have been both validated and widely employed. Given the clinical relevance of PG, it is important that researchers examine pharmacological and behavioral treatments for their safety and efficacy and that clinicians use empirically validated therapies. Multiple neurochemicals, including serotonin, dopamine, norepinephrine, and opioids, and related neurocircuitry, particularly ventral cortico-striatal pathways, have been implicated in PG. The neurobiological rationale for therapies, particularly pharmacological ones, is reviewed with a perspective on the generation of improved prevention and treatment strategies for PG.
Keywords; Addiction, Functional magnetic resonance imaging, Gambling, Impulse control disorder PATHOLOGICAL GAMBLING Gambling can be defined as the act of putting a possession of value at risk in an attempt to gain something of greater value [1]. Historically, excessive gambling has been considered a bad habit or irresponsible behavior. It was not until 1980 [2] that clinicians defined criteria for excessive gambling, termed pathological gambling (PG), in the Diagnostic and Statistical Manual (DSM). Classified as an 'impulse control disorder (ICD) not elsewhere categorized,' estimates of PG prevalence typically range from 0.2-2%, with lower estimates typically found when employing strict diagnostic thresholds [3]. PG shares many core features with drug dependence (DD) and thus PG has been proposed to represent a non-substance or “behavioral” addiction [4, 5]. Proposed core components of addiction include (I) continued engagement in a behavior despite adverse consequences, (II) diminished self-control over engagement in the behavior, (III) compulsive engagement in the behavior, and (IV) an appetitive urge or craving state prior to the engagement in the behavior [5]. Similarities between PG and DD are reflected in the diagnostic criteria which include aspects of tolerance, withdrawal, interference in major areas of life functioning and repeated unsuccessful attempts to cut back or quit. These commonalities between PG and DD suggest that biological features of DD, and therapeutic strategies employed for DD, might be relevant to PG. Up until the past decade, there has been relatively little investigation into the biology and treatment of PG [6]. Early investigations have implicated multiple neurotransmitters, and specific roles for these in PG have been proposed based both on studies of individuals with PG and other available data. Specifically, norepinephrine has been proposed to *Address correspondence to this author at the Departments of Psychiatry1, Neurobiology2, and Child Study Center2, Yale, University School of Medicine, USA; E-mail: [email protected] 1875-6441/12 $58.00+.00
relate to arousal and excitement, serotonin to behavioral initiation and cessation, dopamine to rewarding and reinforcing aspects of behaviors, and opioids to pleasure and urges [7]. Data supporting the involvement of these neurotransmitters in PG are reviewed below. NEUROTRANSMITTERS Specific neurotransmitters have been hypothesized to play specific roles in PG and DD. Norepinephrine has been associated with excitement and arousal [8], dopamine with reward and reinforcing behaviors [9-11], and serotonin in behavioral initiation and cessation (or impulse control) [1215]. Additionally, opioids have been implicated in pleasure and urges [7]. These neurotransmitters may also play other roles, and other neurotransmitters (e.g., glutamate) may also contribute importantly. NOREPINEPHRINE Individuals with PG have been found to have high levels of norepinephrine and/or its metabolites both centrally and peripherally [16, 17], and levels have been found to correlate with measures of extraversion [18]. Noradrenergic measures have also been found to elevate during gambling or gambling-like behaviors (e.g., Pachinko play) in individuals with and without PG [19-21]. Given the link of norepinephrine with excitement and arousal it would be of value to investigate norepinephrine as a potential biomarker of excitability in PG in future studies. Additionally, drugs that target adrenergic regulation may have utility in the treatment of PG (see below), particularly for individuals with PG who may be extroverted and/or exhibit hyperarousal. SEROTONIN Serotonin has been linked to various forms of impulse dyscontrol, including PG. Individuals with disorders characterized by poor impulse control (alcoholism, PG, pyromania) have been found to have low levels of the serotonin metabo© 2012 Bentham Science Publishers
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lite 5-hydroxyindoleacetic acid (5HIAA) [14, 22]. Individuals with poor impulse control, including those with PG, show different behavioral and biological responses to serotonergic drugs. For example, individuals with PG show a blunted prolactin response to clomipramine, a drug which blocks the serotonin and norepinephrine transporters [23]. Individuals with PG, like those with cluster B personality disorders or alcoholism, report a euphoric response or “high” following administration of the serotonergic drug metachlorophenylpiperazine (mCPP), a compound with partial agonist action at 5HT1 and 5HT2 receptors [12]. This behavioral response differs in control comparison subjects who typically report an aversive response. Individuals with PG also show an enhanced prolactin response to mCPP. In brain imaging studies, individuals with impaired impulse control (impulsive aggression or alcoholism) have demonstrated in response to challenges with pro-serotonergic drugs (fenfluramine, meta-chlorophenylpiperazine (m-CPP)) blunted activation of the ventromedial prefrontal cortex (vmPFC), a region implicated in decision-making and impulse control, including in ICDs like PG (see ”Functional Imaging”) [2426]. Given the biological and behavioral responses to serotonergic agents and pre-clinical data implicating serotonin in impulse control, further investigation of the complex serotonin system is warranted in PG. For instance, levels of serotonin 1B receptor in the ventral striatum have been associated with problem gambling severity in PG, suggesting that this receptor may in part contribute to differences in ventral striatal activity observed in PG [27]. DOPAMINE Low cerebrospinal fluid (CSF) levels of dopamine and higher levels of its metabolites have been found in subjects with PG as compared to those without [17], although these findings may not persist when controlling for CSF flow rates [22, 28]. High peripheral levels of dopamine have been observed in problem gamblers while engaging in casino gambling [21]. The pro-dopaminergic drug amphetamine has been found to prime gambling-associated motivations and responses in individuals with PG [29]. An investigation from the same laboratory found that the D2-like dopamine receptor antagonist haloperidol also facilitated gambling-related motivations and responses [30], suggesting that the effects of amphetamine on gambling behaviors might involve other (e.g., D1-like) dopaminergic mechanisms or ones related to other influences (e.g., on noradrenergic systems). Alternatively, individual differences (e.g., related to impulsivity) may influence responses to dopaminergic drugs in PG, as has been suggested in preliminary studies with modafinil [31]. A role for dopamine in ICDs in individuals with Parkinson’s disease (PD) has been investigated [32-34]. ICDs, including PG, have been associated with dopamine agonist use, younger age, earlier age of PD onset, ICDs prior to PD onset, measures of novelty seeking and impulsivity, and personal or family histories of alcoholism [33, 34]. Administration of dopamine replacement therapies may influence aspects of decision-making and impulsivity differently in people with PD and ICDs as compared to those with PD alone [35, 36]. These findings may reflect difference in ventral striatal function, as has been observed in people with PD and PG as compared to those with PD alone [37].
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FUNCTIONAL IMAGING Brain imaging studies suggest that multiple neurocircuits are involved in the pathophysiology of PG. Central to PG, DD and other disorders characterized by impaired impulse control are motivational neural pathways. A central component of motivational neural pathways are cortico-striatothalamo-cortical circuits, with more ventral components particularly relevant to impulsive and reward-driven behaviors [38-40]. Consistently, one of the most frequently implicated brain regions is the vmPFC, and individuals with PG when compared to those without have been found to demonstrate less activation of this brain region when viewing gamblingrelated material [41], performing a test of cognitive control [42], engaging in simulated gambling [43], or performing a decision-making task [44]. These findings are similar to those observed in other groups characterized by impaired impulse control; e.g., the region displaying relatively diminished activation in the PG group in the cognitive control study was largely identical to the distinguishing individuals with and without bipolar disorder [45]. Another frequently implicated brain region in PG neuroimaging studies is the ventral striatum. Individuals with PG as compared to control subjects have demonstrated relatively diminished activation of the ventral striatum when performing simulated gambling or when viewing gambling tapes [43, 46]. Amongst individuals with Parkinson’s disease, those with PG as compared to those without PG showed at baseline relatively diminished raclopride binding (reflecting D2-like dopamine receptor availability) in the ventral striatum, and demonstrated greater raclopride displacement when performing a simulated gambling task, suggesting greater dopamine release during task performance [47]. GENETICS Twin studies have identified a significant heritable component to PG, with about half of the variance appearing genetic in nature for syndromal PG [48, 49]. Twin studies also suggest that genetic and environmental contributions to alcohol dependence and antisocial personality and conduct disorders overlap with those contributing to PG, whereas the co-occurrence between PG and major depression appears predominantly genetic in nature [50-52]. Specific allelic variants have been implicated, albeit inconsistently, in PG [53-57]. It would be of value to further investigate genetic influences in larger samples of individuals with PG (e.g., in genome-wide association studies). TREATMENT Although many individuals may recover without formal intervention [58], behavioral and pharmacological treatments have been shown to be beneficial and early intervention may result in diminished gambling-related problems and improved quality of life. BEHAVIORAL THERAPIES Multiple behavioral interventions and therapies have been investigated in PG [59-63]. Gamblers Anonymous (GA), a 12-step approach based on Alcoholics Anonymous, has been in existence since 1957 and is the most widely available intervention. Studies of its efficacy have been
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sparse, with data indicating that individuals typically attend only for one or two sessions. However, GA attendance in conjunction with formal treatment has been associated with better treatment outcome [64]. Structured behavioral therapies with empirical support include cognitive behavioral therapy (CBT), motivational interviewing, imaginal desensitization in conjunction with motivational interviewing, and brief interventions [63, 65]. The largest study performed to date involved 231 individuals with PG randomized to one of three conditions: therapistdelivered CBT plus GA, CBT manual without therapist delivery plus GA, and GA referral alone. Although all three groups reported diminished gambling over time, those receiving therapist-delivered CBT showed the greatest reductions [66]. PHARMACOLOGICAL THERAPIES Multiple classes of medications have been examined for their tolerability and efficacy in the treatment of PG. Given high frequencies of placebo response, data from placebocontrolled trials offer the best support for or against the efficacies of specific pharmacotherapies; thus, data from placebo-controlled blinded studies are described below. Some drugs (e.g., olanzapine, a drug that blocks dopamine and serotonin receptors and topiramate, a glutamatergic agent) have shown negative results in clinical trials [67-69]. Serotonin reuptake inhibitors have shown mixed results with respect to their efficacy in treating PG, and it is possible that these drugs may have particular benefit for individuals with PG and co-occurring affective conditions (e.g., anxiety disorders – reviewed in [63]). In a modestly sized, randomized, double-blind, placebo-controlled trial, the mood-stabilizing drug lithium was shown to be superior to placebo in the treatment of individuals with co-occurring PG and bipolar spectrum disorders with respect to symptom reductions in both gambling and manic domains [70]. Preliminary data suggest the efficacy of the glutamatergic agent N-acetyl cysteine in the treatment of PG, consistent with preliminary studies in cocaine dependence and nicotine dependence [71]. The most consistent data involve the use of opioid antagonists (naltrexone and nalmefene), which have been found to be superior to placebo in four randomized, double-blind, placebo-controlled trials [63], including the first multi-center pharmacotherapy study of PG, one that involved over 200 subjects. The drugs appear particularly effective for individuals with strong gambling urges and those with a family history of alcoholism [72], findings consistent with those from the alcohol research field. Together, these findings suggest that pharmacotherapy selection in the treatment of PG should be considered and guided by co-occurring symptomatology. Given the contributions of adrenergic and dopaminergic systems to aspects of impulse control, various studies have examined drugs acting on these systems in treatment studies in disorders characterized by impaired impulse control. Though adrenergic agents have not been systematically investigated in PG, given positive findings of adrenergic agents (e.g., atomoxetine, guanfacine) in the treatment of other disorders characterized by impaired impulse control, they warrant further examination in PG. The utility of dopa-
Zakeri and Potenza
minergic drugs might be more limited. On the one hand, dopamine agonists (e.g., pramipexole, ropinirole) have been associated with ICDs including PG in PD, and prodopaminergic drugs like amphetamines have been associated with pro-gambling thoughts and behaviors [29]. On the other hand, the D2-like dopamine receptor antagonist haloperidol has been linked to pro-gambling thoughts and behaviors [30], and a drug with D2-like dopamine receptor antagonistic properties (olanzapine) has not shown efficacy in controlled trials in the treatment of PG [67, 68]. Also, bupropion, a drug with dopaminergic properties, did not differ from placebo in the treatment of PG [73]. Data suggest that indirect modulation of mesolimbic function, through opioid antagonists or glutamatergic agents like n-acetyl cysteine, might be of greater benefit in the treatment of PG. Additional studies targeting other mesolimbic neurotransmitter systems (e.g., serotonin 1B receptors) also warrant consideration, as do drugs that target other relevant circuits (e.g., those involved in stress responsiveness, impulsivity and attention, to name several). CONCLUSION Recent studies into the neurobiology of PG have provided a rational basis for approaching treatment development in PG. Multiple behavioral and pharmacological treatments have shown preliminary efficacy, although larger studies involving more diverse groups of individuals followed for longer periods of time are warranted. As the neurobiological mechanisms of PG are better understood with respect to how they relate to individual differences amongst people with PG, clinicians will be in a better position to select appropriate therapies for specific individuals. DISCLOSURE All authors reported no conflict of interest in the content of this paper. Dr. Potenza has received financial support or compensation for the following: Dr. Potenza has consulted for and advised Boehringer Ingelheim; has financial interests in Somaxon; has received research support from the National Institutes of Health, Veteran’s Administration, Mohegan Sun Casino, the National Center for Responsible Gaming and its affiliated Institute for Research on Gambling Disorders, and Psyadon and Forest Laboratories pharmaceuticals; has participated in surveys, mailings or telephone consultations related to drug addiction, impulse control disorders or other health topics; has consulted for law offices on issues related to addictions or impulse control disorders; has provided clinical care in the Connecticut Department of Mental Health and Addiction Services Problem Gambling Services Program; has performed grant reviews for the National Institutes of Health and other agencies; has guest-edited journal sections; has given academic lectures in grand rounds, CME events and other clinical or scientific venues; and has generated books or book chapters for publishers of mental health texts. FUNDING This work was supported in part by the NIH (R01 DA019039, RL1 AA017539, RC1 DA028279), the VA VISN1 MIRECC, the Connecticut Department of Mental Health and Addiction Services, and a Center of Research
The Neuropsychopharmacology of Pathological Gambling
Excellence Award from the Institute for Research on Gambling Disorders. The content of the manuscript reflect the views and thoughts of the authors and not necessarily those of the funding agencies.
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Revised: August 22, 2011
Accepted: September 20, 2011
