Pharmacological Treatments of Pathological Gambling

Journal of Gambling Studies, Vol. 21, No. 1, Spring 2005 (Ó 2005) DOI: 10.1007/s10899-004-1932-8

Pharmacological Treatments of Pathological Gambling Eric Hollander Erica Sood Stefano Pallanti Nicolo Baldini-Rossi Bryann Baker Department of Psychiatry, Compulsive, Impulsive and Anxiety Disorders Program, Mount Sinai School of Medicine, New York

Medication treatment studies have demonstrated short-term efficacy of various SRIs, opioid antagonists, and mood stabilizers in sub-samples of adult treatment seeking pathological gamblers. Pathological gambling is frequently comorbid with bipolar spectrum disorders, substance abuse/dependence, and attention-deficit/hyperactivity disorder (ADHD), and comorbidity may influence treatment response in pathological gambling. This review focuses on recent research examining the treatment of pathological gambling and highlights methodological challenges for future studies. KEY WORDS: pathological gambling; SSRI; lithium; fluoxamine; PG-YBOCS.

There have been several new pharmacological developments in the treatment of pathological gambling. However, methodological challenges remain in treatment studies. More attention has also been paid to issues of comorbidity with bipolar spectrum and ADHD features, and the impact of this comorbidity on treatment response.

Please address correspondence to Eric Hollander, MD, One Gustave L. Levy Place, Box 1230, New York, NY 10029-6574, U.S.A. E-mail: [email protected].

101 1050-5350/05/0300-0101/0 Ó 2005 Springer Science+Business Media, Inc.

102

JOURNAL OF GAMBLING STUDIES

PHARMACOLOGICAL TREATMENTS: SSRIS Preclinical studies have demonstrated a correlation between low levels of central nervous system serotonin and the suppression of inhibitory responses (Tye, Iverson, & Green, 1979). Results of clinical studies suggest an association between impulsivity and serotonergic dysregulation. It is likely that the serotonergic system is significantly involved in the etiology of PG. Selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy in the treatment of a variety of psychiatric disorders that are believed to be associated with serotonergic (5-HT) dysfunction.

Fluvoxamine In a pilot study of the efficacy of fluvoxamine on gambling urge and gambling behavior conducted by our group, 10 patients with PG completed a trial consisting of an 8-week, single-blind placebo phase, followed by an 8-week, single-blind treatment phase with fluvoxamine (100–200 mg/day) (Hollander et al., 1998b). Seven of the ten completers (70%) were judged treatment responders at the end of the active treatment phase, with a complete abstinence of gambling behavior. The promising results of this pilot study led our group to perform a randomized double-blind crossover trial with fluvoxamine (100–250 mg/day at end point) and placebo in PG patients (Hollander et al., 2000). The percent of improvement on gambling urge and gambling behavior as measured by the PG-CGI improvement score was significantly greater after completing treatment with the active medication (40.6%) than after treatment with placebo (16.6%). Subjects improved more on fluvoxamine (33.4%) than on placebo (28%) as measured by PG-YBOCS, but this did not reach significance. Post-hoc analysis, treating each phase as a separate trial, demonstrated a significant difference between fluvoxamine and placebo in the second, but not the first phase of the trial. These findings suggest that fluvoxamine is well tolerated and may be effective in the treatment of PG in an acute trial, and that an early placebo effect in PG treatment appears to diminish over time.

ERIC HOLLANDER ET AL.

103

Paroxetine The SSRI paroxetine has demonstrated efficacy in the treatment of OCD (Zohar & Judge, 1996). Kim, Grant, Adson, Shin, and Zaninelli (2002) conducted a double-blind placebo controlled study of paroxetine in 45 PG patients. A 1 week placebo lead in phase was followed by 8 weeks of treatment with either paroxetine (20–60 mg/day) or placebo. Statistically significantly greater reductions in the total Gambling Symptom Assessment Scale (G-SAS) and improvements on the CGI were observed at end point on paroxetine as compared to placebo, and a significantly larger number of patients on paroxetine than on placebo were considered to be responders at end point. In response to these results, Grant et al. (2003b) conducted a multi-site, double-blind placebo-controlled trial of paroxetine in 76 patients with pathological gambling. After a 1-week placebo lead in, participants were randomized to either paroxetine (10–60 mg/day) or a matched placebo for 16 weeks. Within the 45 participants that completed the study, there was no statistical significance between the two groups on any of the outcome measures including the CGI, PG-YBOCS and SOGS. Although there was a high rate of responders to paroxetine, there was also a high rate of responders for placebo, which produced no significance between the two groups. On the PG-YBOCS, there were significant treatment group differences at week 4, however, these differences were marginal by week 8. There is no mention of the group differences on the subscales of the PG-YBOCS, the thought/ urge scale or the behavior scale. These scales are of interest because due to financial constraints, a pathological gambler could be unable to engage in gambling behavior, but still be debilitated by thoughts or urges about gambling. Therefore, improvement on the obessional subscale is important. The authors comment that they excluded pathological gamblers with comorbid axis-I disorders, which is not representative of the total pathological gambling population. Additionally, there were significant group differences at baseline on the thought/urge section of the PG-YBOCS. Due to these confounds, a larger sample would be needed to test for efficacy of paroxetine. Citalopram Only one study has been performed on the efficacy of citalopram in the treatment of pathological gambling. Citalopram has

104


proven to be effective in the treatment of OCD (Montgomery, Kasper, Stein, Bang-Hedegaard, & Lemming, 2001), panic disorder (Perna, Bertani, Caldirola, Smeraldi, & Bellodi, 2001), and social phobia (Simon, Sharma, Worthington, Marzol, & Pollock, 2001). Zimmerman and colleagues evaluated 15 PG patients in a 12-week open-label citalopram trial (mean dose of 34.7 mg/day) (Zimmerman, Breen, & Posternak, 2002). They reported a significant improvement on all gambling measures, including the amount of money lost gambling, the number of days gambled, urge to gamble, and preoccupation with gambling. Thirteen of the subjects (86.7%) were rated as responders on the clinician-rated PG-CGI-improvement scale. However, since there is a high placebo response early in the treatment of impulsivity, a double-blind placebo-controlled study is needed to confirm the efficacy of citalopram.

POST-SYNAPTIC 5HT ANTAGONISTS Nefazodone Nefazodone, a phenylpiperazine antidepressant, has mixed noradrenergic/serotoninergic reuptake inhibitor effects. Our group recently conducted an 8-week open-label study of nefazadone in 12 subjects with PG (Pallanti, Baldini-Rossi, Sood, & Hollander, 2002a). Significant improvements were noted in all gambling outcome measures, and 9 out of 12 patients (75%) were rated as responders as measured by a 25% reduction in PG-YBOCS score and PG-CGIimprovement score of 1 or 2 (very much or much improved). However, a larger, controlled trial is needed to determine the efficacy of nefazodone.

OPIATE ANTAGONISTS Naltrexone Two studies of the opioid antagonist naltrexone in pathological gambling have recently been conducted by Kim and colleagues. Naltrexone resulted in significant reductions in gambling urges and behaviors after 6 weeks of open-label treatment (n ¼ 17) (Kim &


105

Grant, 2001a). An 11-week, double-blind, placebo-controlled trial with naltrexone following a 1-week placebo lead-in demonstrated significant improvements on both the patient-rated and clinician-rated CGI and the Gambling Symptom rating Scale based on data from 45 patients (Kim, Grant, Adson, & Shin, 2001b).

ATYPICAL ANTIPSYCHOTICS There have been no controlled trials of atypical antipsychotics to treat pathological gambling. In a case study involving a patient with comorbid pathological gambling and schizophrenia, gambling behavior, as well as psychotic symptoms, lessened when the patient was switched from haloperidol to olanzapine (Chambers & Potenza, 2001). Comorbidity Pathological gambling has been found to co-exist with many other psychiatric disorders, and patients may first seek treatment for a comorbid disorder rather than for the PG itself. Studies have shown that pathological gambling is frequently comorbid with three Axis I disorders: bipolar spectrum disorders, substance abuse/dependence, and attention-deficit/hyperactivity disorder (ADHD) (Sood, Pallanti, & Hollander, 2003). It is essential for clinicians to identify these comorbid disorders in determining the course of treatment because of their contribution to pathological gambling. For example, gamblers with bipolar disorder may experience highs and lows that increase the drive toward obtaining pleasure through gambling and underestimation of harm. Likewise, patients with attention deficit, hyperactivity disorder, experience inattention, and an under arousal state that may be associated with a sense of boredom, causing these individuals to gamble to receive optimal stimulation. Dopamine Reuptake Inhibitors: Bupropion In pathological gamblers with ADHD features, bupropion may be an effective treatment. Recently, Black (in press) conducted an 8-week open-label trial with bupropion with 10 pathological gamblers

106


with ADHD features. Subjects improved significantly on the Y-BOCS, ADHD checklist, and Sheehan Disability Scale. Additionally, 7 reported a CGI-Improvement score of 1 (‘‘very much improved’’) or 2 (‘‘much improved’’) by the end of the study. Of note, participants experienced a increased ability to resist gambling. Further controlled trials of bupropion in pathological gambling need to be conducted in order to confirm its efficacy in this open trial. Mood Stabilizers Previous studies have demonstrated the efficacy of mood stabilizers in various impulse control disorders (Christenson, Popkin, Mackenzie, & Realmuto, 1991; Hollander, Tracy, & Swann, 2003; Stein, Simeon, Frenkel, Islam, & Hollander, 1995), but few methodologically sound trials with mood stabilizers in PG have been conducted to date. Our group recently conducted a 14-week single blind study with 42 PG subjects without comorbid bipolar disorder (Pallanti, Quercioli, Sood, & Hollander, 2002b). Subjects were randomized to either lithium or valproate for the 14-week trial. Both the lithium and the valproate groups showed significant improvement on mean PG-YBOCS score at endpoint, and this improvement did not significantly differ between groups. Fourteen of the 23 patients (60.9%) on lithium and thirteen of the 19 patients (68.4%) on valproate were responders based on a CGI-improvement score of very much or much improved. A 10-week double-blind, placebo controlled study of sustained release-lithium carbonate versus placebo was recently completed by our group (Hollander, Pallanti, Allen, Sood, & Rossi, 2005). Forty bipolar spectrum pathological gamblers were enrolled and 29 completed the study. Sustained release lithium demonstrated good tolerability and efficacy Bipolar spectrum PG patients significantly improved on sustained release lithium carbonate compared to placebo on gambling behavior as measured by total PG-YBOCS, including both thoughts/urges and behavior, and PG-CGI-severity. There was also significant improvement on the CARS-M total and mania subscale. Eleven of 12 patients (91.7%) on lithium were responders (PG-CGI-improvement) versus 6 of 17 (35.3%) on placebo. Of note, there was significant positive correlation between improvement in impulsivity (PG-YBOCS) and improvement in affective instability


107

(CARS-M) on lithium. It is unclear whether improvement in impulsivity caused improvement in affective instability, or whether improvement on affective instability caused improvement on impulsive gambling.

CONCLUSION Medication treatment studies performed in pathological gambling have demonstrated the short-term efficacy of various SRIs, opioid antagonists and mood stabilizers in a sub-sample of adult pathological gamblers seeking treatment. Methodological weaknesses within some of these studies suggest the need for larger doubleblind, placebo-controlled studies to confirm the efficacy of these medications. It is difficult to determine whether a medication is efficacious in treating pathological gambling because often, as with most impulse control disorders, there is a high rate of placebo responders in the beginning of treatment. This placebo effect has been evidenced in a double-blind cross-over study by Hollander et al. (2000) using fluoxamine, in which there is no difference between the medication and the placebo in the first phase. With time, the placebo effect lessens and the positive effects of the medication are evidenced. However, in open-label studies there is no placebo group to compare to and, with short studies, it is difficult to identify whether the drug is advantageous or whether it is a placebo effect. Although certain psychotropic medications may be effective in treating pathological gamblers during a trial lasting 8–12 weeks, few studies have attempted to determine whether these medications are effective over an extended treatment period. Future studies are needed in order to determine the efficacy of such medications in the long-term treatment of pathological gambling. Additionally, even though the PG-YBOCS has been determined to yield reliable results in pathological gambling, issues arise with this measure. There are two sections within the PG-YBOCS: a section with urge/thought related questions about gambling and a section on gambling behavior. Many pathological gamblers dig themselves into bankruptcy due to their excessive gambling behavior (Maccallum & Blaszczynski, 2003). Because of their financial situation, they are

108


unable to engage in gambling behavior and therefore, score low on the behavior section while still scoring high on the thought/urge section. Therefore, it is our recommendation that, as a primary outcome measure, only the thought/urge section of the PG-YBOCS should be employed. The total score and behavioral score should be used as secondary outcome measures. Because psychopharmacological research studies have evaluated only a subsample of patients with PG, the results cannot be automatically generalized to the entire population of pathological gamblers. Approximately half of all pathological gamblers abuse alcohol or other substances; yet, subjects with a diagnosis of alcohol or substance abuse/dependence were excluded from many of the psychopharmacological treatment studies of pathological gambling. In addition, there may be a factor that distinguishes pathological gamblers seeking treatment from those who do not. As of yet, we have knowledge concerning only the effectiveness of these medications in treating pathological gamblers who choose to seek treatment. In addition to methodological weaknesses within medication studies, there are also other challenges in treating patients afflicted with pathological gambling. Treatment compliance is a large issue, especially in those with bipolar features (Grant, Kim, & Potenza, 2003a). In many cases, a comorbid condition may determine the effectiveness of a medication used to treat pathological gambling. Because PG has been found to have a high comorbidity with other psychiatric disorders, the most effective and best tolerated medication may vary depending upon the comorbidity (Hollander, Begaz, & Decaria, 1998a). While SRIs such as fluvoxamine may be effective in treating PG with a comorbid obsessive-compulsive spectrum disorder or OCD features, SRIs may not be optimal treatment of PG with comorbid ADHD or bipolar spectrum disorder. A patient with comorbid ADHD may be treated with a stimulant such as dextroamphetamine and methylphenidate, or a dopaminergic medication such as bupropion, in combination with an SRI (Hollander et al., 1998a). Clinicians must be especially careful when treating patients at risk for bipolar disorder. It is possible that SRI-induced manic behaviors could emerge in pathological gamblers with a history of, or at risk for, mania or hypomania. Gambling urge and gambling behavior increased in two pathological gamblers with comorbid cyclothymia


109

during treatment with fluoxamine (Hollander et al., 1998). A mood stabilizer such as lithium or valproate may be a better treatment option for patients presenting with comorbid bipolar disorder. Because pathological gambling is not yet recognized widely as a psychiatric disorder, few individuals with PG seek psychiatric treatment, and those who do often seek treatment for a comorbid disorder. Furthermore, pharmacotherapy is a fairly new approach to the treatment of PG, and in the past, patients were more likely to be referred to gamblers anonymous than to be treated with medication. Therefore, the little that is known about psychopharmacological treatments for pathological gambling has been obtained from research studies. As the awareness of PG as a psychiatric disorder increases and psychiatrists begin to treat pathological gamblers with medication, it is expected that more patients will seek psychiatric treatment, and the experiences of psychiatrists treating this population will complement the knowledge obtained through research studies. ACKNOWLEDGMENTS Some of the research included in this manuscript was supported in part by NIDA (5 RO1 DA10234-03), Solvay Pharmaceuticals, and a grant (5 MO1 RR00071) for the Mount Sinai General Clinical Research Center from the National Center for Research Resources, National Institutes of Health. REFERENCES Black, D. W. (2004). An open-label trial of bupropion in the treatment of pathological gambling. Journal of Clinical Psychiatry, 24, 108–110. Chambers, R. A., & Potenza, M. N. (2001). Schizophrenia and pathological gambling. American Journal of Psychiatry, 158, 487–498. Christenson, G. A., Popkin, M. K., Mackenzie, T. B., & Realmuto, G. M. (1991). Lithium treatment of chronic hair pulling. Journal of Clinical Psychiatry, 52, 116–120. Grant, J. E., Kim, S. W., & Potenza, M. N. (2003a). Advances in the Pharmacological Treatment of pathological gambling. Journal of Gambling Studies, 19, 85–109. Grant, J. E., Kim, S. W., Potenza, M. N., Blanco, C., et al. (2003b). Paroxetine treatment of pathological gambling: A multi-centre randomized controlled trial. International Clinical Psychopharmacology, 18, 243–249. Hollander, E., Begaz, T., & DeCaria, C. M. (1998a). Pharmacological approaches in the treatment of pathological gambling. CNS Spectrums, 3, 72–80. Hollander, E., DeCaria, C. M., Mari, E., Wong, C. M., Mosovich, S., Grossman, R., et al. (1998b). Short-term single-blind fluvoxamine treatment of pathological gambling. American Journal of Psychiatry, 155, 1781–1783.

110


Hollander, E., DeCaria, C. M., Finkell, J. N., Begaz, T., Wong, C. M., & Cartwright, C. (2000). A randomized double-blind fluvoxamine/placebo crossover trial in pathologic gambling. Biological Psychiatry, 47, 813–817. Hollander, E., Pallanti, S., Allen, A., Sood, E., & Rossi, N. B. (2005). Does sustained-release lithium reduce impulsive gambling and affective instability vs. placebo in pathological gamblers with bipolar spectrum disorder? American Journal of Psychiatry, 162, 137–145. Hollander, E., Tracy, K. A., Swann, A. C., et al. (2003). Divalproex in the treatment of impulsive aggression: Efficacy in cluster B personality disorders. Neuropsychopharmacology, 28, 1186– 1197. Kim, S. W., & Grant, J. E. (2001a). An open naltrexone treatment study in pathological gambling disorder. International Clinical Psychopharmacology, 16, 285–289. Kim, S. W., Grant, J. E., Adson, D. E., & Shin, Y. C. (2001b). Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biolological Psychiatry, 49, 914–921. Kim, S. W., Grant, J. E., Adson, D. E., Shin, Y. C., & Zaninelli, R. (2002). A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling. Journal of Clinical Psychiatry 2002, 63, 501–507. Maccallum, F., & Blaszczynski, A. (2003). Pathological gambling and suicidality: An analysis of severity and lethality. Suicide Life Threatening Behavior, 33, 88–98. Montgomery, S. A., Kasper, S., Stein, D. J., Bang-Hedegaard, K., & Lemming, O. M. (2001) Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder. International Clinical Psychopharmacology, 16, 75–86. Pallanti, S., Baldini-Rossi, N., Sood, E., & Hollander, E. (2002a). Nefazodone treatment of pathological gambling: A prospective open label controlled trial. Journal of Clinical Psychiatry, 63, 1034–1039. Pallanti, S., Quercioli, L., Sood, E., & Hollander, E. (2002b). Lithium and valproate treatment of pathological gambling: A randomized single-blind study. Journal of Clinical Psychiatry, 63, 559–564. Perna, G., Bertani, A., Caldirola, D., Smeraldi, E., & Bellodi, L. (2001). A comparison of citalopram and paroxetine in the treatment of panic disorder: A randomized, single-blind study. Pharmacopsychiatry, 34, 85–90. Simon, N. M., Sharma, S. G., Worthington, J. J., Marzol, P. C., & Pollack, M. H. (2001). Citalopram for social phobia: A clinical case series. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 25, 1469–1474. Sood, E. D., Pallanti, S., & Hollander, E. (2003). Diagnosis and treatment of pathological gambling. Current Psychiatry Reports, 5, 9–15. Stein, D. J., Simeon, D., Frenkel, M., Islam, M. N., & Hollander, E. (1995). An open trial of valproate in borderline personality disorder. Journal of Clinical Psychiatry, 56, 506–510. Tye, N. C., Iverson, S. D., & Green, A. R. (1979). The effects of benzodiazepines and serotonin manipulations on punished responding. Neuropharmacology, 18, 689–695. Zimmerman, M., Breen, R. B., & Posternak, M. A. (2002). An open-label study of citalopram in the treatment of pathological gambling. Journal of Clinical Psychiatry, 63, 44–48. Zohar, J., & Judge, R. (1996). Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. British Journal of Psychiatry, 169, 468–474.