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Current Pharmaceutical Design, 2011, 17, 1389-1395
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Psychopharmacological Treatment in Pathological Gambling: A Critical Review
Division of Addictology Department of Mental Health and Psychiatry University Hospitals of Geneva Rue verte, 2, 1205 Geneva. Switzerland Abstract: Given the rates of pathological gambling and its impact on affected individuals and their relatives, effective treatments are
needed. There are, however, no approved pharmacological treatments for pathological gambling. This paper describes the development of
pharmacological treatments for pathological gambling and is based on a review of the literature published in the past 10 years. Important
studies were carried-out on antidepressants, mood stabilizers, and antipsychotic agents. In the absence of comorbid psychiatric disorder,
these studies did not conclude to the efficacy of these psychotropic drugs. A possible efficacy of opiate antagonist treatment for patho-
logical gambling has been replicated in a number of placebo-controlled studies. Preliminary results on N-acetyl cysteine, Memantine and
Topiramate produced significant improvement for pathological gamblers and may open new avenues for treatment.
Keywords: Pathological gambling, drugs, antidepressant, lithium, valproate, carbamazepine, naltrexone, nalmefene, topiramate, glutamate,
N-acetylcysteine.
INTRODUCTION
studies included participants with a diagnosis of PG. Follow-up Pathological gambling (PG) is classified as an impulse control disorder in the Diagnosis and Statistical Manual of Mental Disorder Studies were heterogeneous in pathological gambling diagnosis (DSM-IV-TR; American Psychiatric Association, 2000). Lifetime criteria, outcome measures and comorbid psychiatric disorder prevalence of pathological gambling is estimated to be about 1 % [1]. To date, there is no well-validated pharmacotherapeutic treat-ment of PG. The aim of this review is to summarize the latest 10 Antidepressants
years developments on PG pharmacotherapy research. Selective Serotonin Reuptake Inhibitors (SSRIs) have demon- strated their efficacy in several psychiatric disorders such as depres- sion, obsessive-compulsive disorders (OCD), and anxiety disorders Two reviewers were separately engaged in this review, follow- [2]. Using SSRIs to treat PG, is supported by several hypotheses ing the same bibliographic search and data extraction protocol. related to serotoninergic dysfunction in PG [3, 4]. In the past decade, there have been 4 open-label trials that stud- Bibliographic search
ied the efficacy of antidepressants in PG. A 12 weeks open-label 1) consisted of a computerized
study on 15 patients [5] reported that Citalopram appeared to be an screening Medline database from December 2010 to January effective treatment for PG, independentl of its antidepressant prop- 2011,limited to the last ten years published articles in English, and erties. An open-label pilot study [6] on Escitalopram (12 weeks) in used the following queries: “treatment AND pathological gam- a sample of 13 subjects with concurrent anxiety disorders con- bling”, “pharmacotherapy AND pathological gambling”, “drugs cluded in its efficacy on both gambling and anxiety symptoms. The AND pathological gambling”, “antipsychotic AND pathological efficacy of Escitalopram on PG was also supported by a 10 weeks gambling”, “SSRI AND pathological gambling”, “antiepileptic open label trial [7] on 19 non-depressed outpatients. Nefazodone, AND pathological gambling”, “mood stabilizer AND pathological an antidepressant with a specific 5-HT2 receptor antagonism had gambling”, “lithium AND pathological gambling”, “Valproate positive effects during an 8 weeks trial on gambling urges and be- AND pathological gambling”, “ antidepressant AND pathological havior, and mood and anxiety symptoms in a sample of 14 patients gambling”, “Topiramate AND pathological gambling” yielding to (with low baseline levels of co-occurring depression, binge eating, an initial pool of 1294 results. Of the 71 potential articles, 27 stud- ies (18 controlled and 9 non controlled) met criteria for inclusion: Four double blind randomized controlled trials (RCTs) com- (a) the target problem was pathological gambling, (b) the treatment pared SSRIs with placebo. Fluvoxamine [9] , in a 24 weeks trial was pharmacological, and (c) the study described outcomes related showed no significant superior improvement comparing to placebo on money or time spent in gambling behaviors. Studies on Paroxet- Data Extraction
ine reported divergent findings. While an 8 weeks study on 45 pa-tients [10] found significant superiority of Paroxetine in gambling Data collected from the 27 selected studies included (a) study symptoms, another 16 weeks multicentric trial [11] found no sig- design, (b) sample size, (c) treatment, (d) PG diagnosis criteria, (e) nificant superiority of Paroxetine versus placebo. Sertraline failed comorbidities, (f) targeted population, (g) study methodology to show superiority in a 24 weeks placebo-controlled trial on 66 (founding, randomization, blinding, exclusion criteria, treatment patients [12]. The observed response rates were high in placebo duration, follow up), and (h) drop-out rates and (i) efficacy results. The antidepressant Bupropion slow release is a selective reup- take inhibitor of Dopamine and Noradrenaline. It is prescribed to Of the 27 included studies, 18 were controlled trials (n=1113) (Table 1) and 9 were open label trials (n=163) (Table 2). The
manage nicotine withdrawal symptoms and addiction [13]. An eight weeks open-label trial [14] on 10 subjects without depression found a positive impact on pathologic gambling disorder. These positive *Address correspondence to this author at the Division of addictology De- findings were not supported by a placebo-controlled study on 39 partment of mental health and psychiatry University Hospitals of Geneva, gamblers with depression [15]. The observed response rate was also Rue verte, 2, 1205 Geneva. Switzerland; Tel: 0041223725550; Fax: 0041223202840; E-mail: Yasser.khazaal@hcuge.ch high in placebo group 47% [15]. A RCT study on 36 patients 1381-6128/11 $58.00+.00
2011 Bentham Science Publishers Ltd.
1390 Current Pharmaceutical Design, 2011, Vol. 17, No. 14
Achab and Khazaal
Bibliographic research
N=1294
Pertinent title
N=71
Included studies
Excluded studies
N=27
-Non pertinent n=16
-controlled n=18
-Case reports n=11
- non controlled n=9
-Reviews n=17
Fig. (1). Bibliographic search.
Controlled Trials on Pharmacological Treatments for Pathological Gambling.
Methodology Outcomes
Exclusion Criteria
Treatment
Last Measure
Drop-out
Studies N Age
Country Treatment PG
Diagnosis
Comorbidities
Randomization
Related to Psychiatric
Duration
Rates (%)
or Addictive Disorders
Controlled trials
Mood stabilizers
Psychopharmacological Treatment in Pathological Gambling
Current Pharmaceutical Design, 2011, Vol. 17, No. 14 1391
(Table 1) Contd….
Methodology Outcomes
Exclusion Criteria
Treatment
Last Measure
Drop-out
Studies N Age
Country Treatment PG
Diagnosis
Comorbidities
Randomization
Related to Psychiatric
Duration
Rates (%)
or Addictive Disorders
Opioid antagonists
Glutamatergic agents
Bupropion
suicidal or aggressive disorder, psychotic or Topiramate vs antidepressant
1392 Current Pharmaceutical Design, 2011, Vol. 17, No. 14
Achab and Khazaal
(Table 1) Contd….

Methodology Outcomes
Exclusion Criteria
Treatment
Last Measure
Drop-out
Studies N Age
Country Treatment PG
Diagnosis
Comorbidities
Randomization
Related to Psychiatric
Duration
Rates (%)
or Addictive Disorders
Antipsychotics
Studies Were Assessed for Randomization and Double- blinding . Studies Were Given a Score of A (yes), B (No), NA (Not Applicable) for Open Label Trials , or N/s (Not Specified).Study Founding was Assessed, and Studies were Given a Score of A ( Pharmaceutical Support), or B (Other Financial Support).Drop-out Rates Concern Subjects who have Discontinued the Study. Numerical Datas have been Rounded-off. Abbreviations:5-HT antagonist = serotoninergic antagonist, ADHD= attention Deficit Hyperactivity Disorder, CCPGQ= Criteria for Control of pathological Gambling Questionnaire, CGI = Clinical Global Impressions scale, CGI-I= Clinical Global Impressions-Improvement scale, CGI-S= Clinical Global Impressions-Severity scale, DSM IV= Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, DSM IV TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth revised edition, GA= Gamblers Anonymous, GBD= Gambling Behavior Diary, G-SAS= Gambling Symptom Assessment Scale, GUQ= the Gambling Urge Questionnare, HAM-A= Hamilton Rating Scale for Anxiety, HAM-D =Hamilton Rating Scale for Depression, HDRS= Hamilton Depression Rating Scale, MAOI= Monoamine Oxidase Inhibitor, MDD= Mood Depressive Disorder, N= sample size, NA= Not Applicable, NODS= National Opinion Research center DSM Screen for Gambling Problems, NS= non significant,N/s= Not specified (for comorbities.check exclusion criteria), OCD= Obsessive Compulsive Disorder, PG= Pathological Gambling, PG-BSRS= Pathological Gambling Behavioral Self-Report Scale, PG-VACS= Patological Gambling Visual Analog Craving Scale, PG-YBOCS= Pathological Gambling modifications of the Yale Brown Obsessive Compulsive Scale, S= significant, SCI= Structured Clinical Interview, SCID = Structured Clinical Interview for DSM IV, SDI= sheehan Disability Inventory, SDS= Sheehan Disability scale, SOGS= South Oaks Gambling Screen, SSRI= Selective Serotonin Reuptake Inhibitor, SSPI= Semi-Structured Psychiatric Inventory,TLFB= TimeLine Follow Back, vs= versus, wk= week. with PG found no difference between Bupropion and Naltrexone on mg/day and titrated upward until maximum symptom improvement or 250 mg/day was achieved. The second RCT, an 18 weeks trial, [28] included 77 subjects with co-occurring mood, anxiety and Mood Stabilizers
impulse control disorders, treated with Naltrexone (50, 100 or 150 Several features are shared by PG and bipolar disorder such as mg/day) or placebo. Men and women did not differ significantly in impulsivity, mood swings and grandiose thinking [17, 18] leading their response to Naltrexone. Low-dose Naltrexone (50 mg/day) to the assessment of mood stabilizer agents in PG. appeared as efficacious as higher doses (100 mg/day and 150 A 10 weeks Carbamazepine open-label trial [19] on 8 outpa- mg/day), and all doses were well tolerated. In contrast, a high rate of side effects was reported in the first study [27] probably due to tients without bipolar disorder nor depression, reported a significant higher Naltrexone dosage (188 mg/day on average). efficacy on gambling. Thirty-eight percent of the participants were dropped-out from the study due to side effects. Two large 16 weeks RCTs on Nalmefene [29, 30] (respectively In a single blind 14 weeks controlled trial [17], both Lithium n=207 and 233), an opiate antagonist, were carried-out. In the first study [30] low-dose Nalmefene (25 mg/day) or 50 mg/day appeared and Valproate showed significant improvement (response rate: 61% more efficacious than placebo. Higher dose (100 mg/day) resulted and 68% respectively), without any group differences, at the Patho-logical Gambling- Yale Brown Obsessive Compulsive Scale (PG- in more frequent intolerable side effects leading to study discon-tinuation. The second study [29] with lower doses (20 or 40 mg Nalmefene or placebo), failed to show statistically significant dif- Two RCTs on patients with concomitant bipolar disorder II or ferences from placebo on outcome measures. Post hoc analyses of cyclothymia [20, 21] reported a greater improvement with lithium only participants who received 40 mg/day of the medication for at in comparison with placebo on Y-BOCS scores. Improvement in least 1 week demonstrated that Nalmefene resulted in significantly gambling severity was significantly correlated with improvement in greater reductions on the primary outcome measures. Atypical Antipsychotics
Opioid Antagonists
Atypical antipsychotics modulate dopamine (D2 receptor an- The Involvement of Mu-opioid system in reward processes tagonism) and serotonin (5HT2A and/or 5HT2C antagonism) neu- leads to hypothesized possible impact of opioid antagonists on ad- ronal system were involved in impulse control disorders. Two dictive behaviors and PG [22]. A recent Cochrane review concludes RCTs on gamblers without comorbid psychosis found that Olanzap- that Naltrexone is an effective and safe strategy in alcoholism ine was not superior to placebo in the treatment of pathological Two non controlled trials on Naltrexone reported favorable Glutamatergic Agents
Fifty-two, mostly male, subjects received during 11 weeks a Glutamate and its receptors seem to play a crucial role in addic- cognitive-behavioral therapy (CBT) in association of Naltrexone or tive disorders [33, 34]. Behaviors with a compulsive and/or addic- placebo. No significant group differences were found on any alco- tive component can characteristically be triggered by environmental hol or gambling-related outcomes at post-treatment or at the one cues [35]. Recent research has highlighted the central role of the year follow-up. However, a strong time effect was found suggesting glutamatergic system in mediating this cue reactivity (For more that treatment, in general (including its cognitive-behavioral com- details, see paper on Topiramate in the same issue). N-acetylcysteine (NAC)
Superiority of Naltrexone on placebo was found in 2 other trials N-acetylcysteine (NAC) is an amino acid and cysteine pro-drug without concomitant CBT. The first one [27], a 11 weeks RCT, involved 45 gamblers, mostly women. Naltrexone was started at 25 that increases extracellular levels of glutamate in the nucleus ac-cumbens and reduces reward-seeking behavior in rats with cocaine Psychopharmacological Treatment in Pathological Gambling
Current Pharmaceutical Design, 2011, Vol. 17, No. 14 1393
Open Label Trials on Pharmacological Treatments for Pathological Gambling. Study Founding was Assessed, and Studies
were Given a Score of A (pharmaceutical Support), or B (Other Financial Support). Drop-out Rates Concern Subjects
who have Discontinued the Study. Numerical Datas have been Rounded-off.
Methodology Outcomes
Treatment
Proportion
Exclusion Criteria Related to Psychiatric or
Studies N
Country Treatment
Diagnosis
Comorbidities Founding
Duration
Measure at
Males (%)
Addictive Disorders
Open-label Trials
Infrequent gambling,other psychotropic medica- tion, suicidality, current Axis I disorder, bipolar disorder, psychotic disorder, dementia, substance abuse in the 3 months, psychotherapy in the 3 months, previous citalopram or escitalopram, investigational medication or depot neuroleptic in the 3 months, fluoxetine in the 6 weeks, other Schizophrenia, schizoaffective disorder, bipolar disorder, current substance dependence, antisocial personality disorder, organic mental disorder, suicidality, MDD, previous escitalopram, , individual or group psychotherapy in the 3 months, psychotropics in the 2 weeks, MAOI in 5-HT antagonist
Current bipolar disorder, psychosis, organic mental disorders, suicidality, significant auto- Mood stabilizers
History of psychosis, current drug dependence, organic mental disorder, suicidal risk, mood disorder, past carbamazepine, individual or group therapy for PG in the last 3 months before, psychotropic medications 2-4 weeks before, Opioid antagonists
Other current Axis I disorder, psychotropic last 4 weeks, individual or group psychotherapy, gamblers anonymous, drug abuse in the 3 months severe depression, other untreated mental health problem, substance abuse (other than nicotine and Glutamatergic agents
Lifetime bipolar disorder, dementia, psychosis, current substance abuse, psychotherapy in the 3 Bupropion
Current MDD, schizophrenia, primary anxiety disorder, bipolar disorder, past month substance use disorder, severe personality disorder, current Abbreviations:5-HT antagonist = serotoninergic antagonist, ADHD= attention Deficit Hyperactivity Disorder, CCPGQ= Criteria for Control of pathological Gambling Questionnaire, CGI = Clinical Global Impressions scale, CGI-I= Clinical Global Impressions-Improvement scale, CGI-S= Clinical Global Impressions-Severity scale, DSM IV= Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, DSM IV TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth revised edition, GA= Gamblers Anonymous, GBD= Gambling Behavior Diary, G-SAS= Gambling Symptom Assessment Scale, GUQ= the Gambling Urge Questionnare, HAM-A= Hamilton Rating Scale for Anxiety, HAM-D =Hamilton Rating Scale for Depression, HDRS= Hamilton Depression Rating Scale, MAOI= Monoamine Oxidase Inhibitor, MDD= Mood Depressive Disorder, N= sample size, NA= Not Applicable, NODS= National Opinion Research center DSM Screen for Gambling Problems, NS= non significant,N/s= Not specified (for comorbities.check exclusion criteria), OCD= Obsessive Compulsive Disorder, PG= Pathological Gambling, PG-BSRS= Pathological Gambling Behavioral Self-Report Scale, PG-VACS= Patological Gambling Visual Analog Craving Scale, PG-YBOCS= Pathological Gambling modifications of the Yale Brown Obsessive Compulsive Scale, S= significant, SCI= Structured Clinical Interview, SCID = Structured Clinical Interview for DSM IV, SDI= sheehan Disability Inventory, SDS= Sheehan Disability scale, SOGS= South Oaks Gambling Screen, SSRI= Selective Serotonin Reuptake Inhibitor, SSPI= Semi-Structured Psychiatric Inventory,TLFB= TimeLine Follow Back, vs= versus, wk= week. dependence [34]. It also reduces cue-induced craving in individuals PG-YBOCS score) at end point. They were randomized to NAC or with cocaine addiction [36]. Twenty-seven subjects with PG were placebo. Of those assigned to NAC, 83.3% still met responder crite- treated in an 8-week open-label trial of NAC [37]. Sixteen subjects ria at the end of the double-blind phase, compared with only 28.6% (59.3%) met responder criteria (> or = 30% reduction in 1394 Current Pharmaceutical Design, 2011, Vol. 17, No. 14
Achab and Khazaal
Memantine
on mood symptoms. The results obtained from patients with bipolar Memantine, a N-methyl D-aspartate (NMDA) receptor antago- disorder cannot be generalized to PG. Other RCTs on mood stabi- nist in the striatum may have possible effects on addictive behav- lizers in PG should be conducted in patients without bipolar disor- iors and PG [33, 38]. Twenty-nine subjects with comorbid psychiat- ric disorders (Table 2) were enrolled in a 10-week open-label
The most promising results of the decade were probably drawn treatment study of Memantine [39].Twenty-eight of the 29 subjects from studies on agents acting on the glutamatergic system such as completed the study. Memantine treatment was associated with N-acetylcysteine, Memantine and Topiramate. The preliminary results issued from this track seem to of high interest and warrant further steps of development. Topiramate
In addition, further studies on PG should improve characteriza- Topiramate is an antiepileptic treatment that has been tested in tion of gamblers subtype. One could hypothesize that treatment several addictive [40-42], impulse control and eating disorders [43- response depends on possible subtypes such as impulsive, obses- 45]. Because of this
-amino-3-hydroxy-5-methyl-4-isoxazole- sive-compulsive, and addictive subtype [52]. Impulsive subtype propionic acid (AMPA) receptor antagonist action [46], Topi- may respond preferentially to mood stabilizers, obsessive-compul- ramate’s effect is expected to act primarily on automatic processes sive subtype may be preferentially responsive to antidepressants underlying cue-triggered addictive behavior [47]. A 12 weeks study and the addictive subtype may respond best to anti-addiction agents on 31 males aimed to compare Topiramate versus Fluvoxamine such as opioid receptor antagonists [52]. (SSRI) in the treatment of PG [48]. Nine of 12 Topiramate comple-ters (about 15 allocated to Topiramate) reported full remission of ABBREVIATIONS
gambling behavior. A significant improvement was observed in the Topiramate group at the 12-week visit as compared with baseline. Six of eight Fluvoxamine completers (about 16 allocated to Fluvox-amine) reported a full remission. It was not found between group Pathological Gambling- Yale Brown Obsessive DISCUSSION
CONFLICT OF INTEREST
Controlled studies on antidepressant agents mostly conclude on lack of superiority versus placebo. This finding is observed despite high dosage (i.e. 60 mg/day paroxetine) and trials duration extended REFERENCES
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Accepted: April 5, 2011
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