Medications for Gambling Disorder Mayumi Okuda Benavides M

‹#› Medications for Gambling Disorder Mayumi Okuda Benavides, M. D. Gambling Disorders Clinic NYSPI Chapman Perelman Fellow

‹#› Disclosures • Chapman Perelman Foundation • OASAS (Office of Alcoholism and Substance Abuse Services) • Co Investigator 2 R 01 HD 060072 06 A 1(Martins, PI). National Institute of Child Health and Human Development (NICHD). Predictors of Impulsive Behavior Among Youth • New York Council on Problem Gambling

‹#› Definition • Persistent and recurrent problematic gambling behavior leading to clinically significant impairment or distress, as indicated by the individual exhibiting four (or more) of the following in a 12 month period: – Needs to gamble with increasing amounts of money in order to achieve the desired excitement (tolerance) – Is restless or irritable when attempting to cut down or stop gambling (withdrawal) – Has made repeated unsuccessful efforts to control, cut back, or stop gambling – Is often preoccupied with gambling (e. g. , having persistent thoughts of reliving past gambling experiences, handicapping or planning the next venture, thinking of ways to get money with which to gamble)

‹#› Definition • Persistent and recurrent problematic gambling behavior leading to clinically significant impairment or distress, as indicated by the individual exhibiting four (or more) of the following in a 12 month period: – Often gambles when feeling distressed (e. g. , helpless, guilty, anxious, depressed) – After losing money gambling, often returns another day to get even (“chasing” one’s losses) – Lies to conceal the extent of involvement with gambling – Has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling – Relies on others to provide money to relieve desperate financial situations caused by gambling

‹#› Definition • Gambling behavior is not better explained by a manic episode • Specify if: Episodic: Meeting diagnostic criteria at more than one time point, with symptoms subsiding between periods of gambling disorder for at least several months Persistent: Experiencing continuous symptoms, to meet diagnostic criteria for multiple years

‹#› Prevalence • Gambling: 70– 90% of adults gamble sometime in their lives • Lifetime prevalence rates of Gambling Disorder: 0. 1% to 5. 1% (1% in the United States) • Incidence: introduction of a new gambling venue/new form of gambling • Prevalence rates among general psychiatry patients: 6. 7– 12% • Among substance abusers, prevalence rates between 7% and 39%

‹#› Genetics • Twin study evaluated the concordance for lifetime pathologic gambling in a sample of 6744 males, which included 1874 monozygotic twin pairs and 1498 dizygotic twin pairs – Lifetime history 1% – 10% dizygotic cotwins of men – 23% of the monozygotic • A twin study that included 867 monozygotic twin pairs and 1008 dizygotic twin pairs found that genetic influences accounted for 49% of the variation in liability, no sex differences

‹#› Comorbidities • National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) • General population, sample resembling the US Census • Among those with Gambling Disorder: • Mood (49. 62%) and anxiety (41. 30%) • Substance use disorders: alcohol (73. 22%) and drug use disorder (38. 10%) • Personality disorders

‹#› Medications • To date, there’s no FDA approved medication to treat gambling disorder

‹#› Clinical Scenario Angela a 34 year-old Black Honduran female, who is widowed and has 3 children, works as a manager in a store. She presented to the clinic seeking treatment for gambling disorder. Gambling (slot machines) has resulted in significant financial loss and problems at work. She reports a history of childhood neglect and intimate partner violence. She reports severe emotional, physical (strangled her) and sexual abuse perpetrated by her husband. Her husband was killed 6 years ago. She describes symptoms consistent with major depression and PTSD (nightmares, flashbacks like feeling his husband’s hands around her neck). She acknowledged that she gambles as a way to “escape” from painful memories from the past.

‹#› Medications: Antidepressants • Initial research demonstrated that medications had a role in the treatment of gambling disorder’s coexisting depression • Small trials of selective serotonin reuptake inhibitors (SSRIs) found some effect in reducing gambling behaviors independent of their effect on mood anxiety disorders

‹#› Medications: Antidepressants • Fluvoxamine was studied in a randomized, placebo controlled study of 10 men with gambling disorder • Crossover design, 8 weeks of fluvoxamine and 8 weeks of placebo • Significantly greater percent improvement in overall gambling severity on the Pathological Gambling Clinical Global Impression scale • However, the difference between the treatment and placebo groups was only significant in the second phase of the trial, suggesting that there was an initial placebo effect that diminished with time

‹#› Medications: Antidepressants • Sertraline trial: large placebo effect was also noted • Response rate was the same for sertraline and placebo • Open label studies with other SSRIs including Citalopram and Fluoxetine have been found effective for the treatment of non depressed individuals with gambling disorder • A report of fluoxetine in combination with psychotherapy was associated with higher remission rates • Small, open label trial of bupropion also suggested possible benefits

‹#› Medications: Antidepressants Summary • In summary, all these studies have been limited by: • Small sample size • Short follow up • In some cases study design • Thus, confirmation in larger randomized, controlled trials with extended follow up is required before definitive recommendations can be made

‹#› Medications: Mood Stabilizers • A randomized trial suggested that in patients with bipolar spectrum disorder (but not bipolar I disorder) and gambling disorder, lithium could be beneficial • Topiramate had some efficacy in a randomized controlled trial

‹#› Medications: Antipsychotics • Olanzapine was not more effective than placebo in another randomized trial • Aripiprazole: FDA warning

‹#› Medications: Opioid Antagonists • Naltrexone: one open label and three small randomized, placebo controlled trials found that treatment with naltrexone leads to improvement on gambling symptom assessment scales • Check liver function tests! • Family member with alcohol use disorder • Decreased urges to gamble

‹#› Medications: Opioid Antagonists • A randomized double blind trial of nalmefene (n=207) found that nalmefene 25 mg per day significantly reduced gambling assessment scores over a 16 week trial period compared with placebo • Higher doses of nalmefene were not more effective but caused more side effects

‹#› Medications leading to Gambling Disorder • In recent years, there has been increasing evidence and awareness that individuals with Parkinson’s Disease or Restless Legs Syndrome are at increased risk of developing one or more of four major behavioral addictions • The most common ones include gambling disorder, excessive buying, hypersexuality and eating disordered behaviors (binge eating) • These behaviors range widely in severity, but can lead to devastating consequences, including financial ruin, divorce, loss of employment, and increased health risks

‹#› Clinical Scenario Adam a 56 year-old White, separated male, with 2 adolescent children, working full time as an attorney reports losing all of his savings, his children’s college funds due to gambling losses (cards, craps in casino) during the past 2 years. He reports gambling recreationally when he was young. During the past 2 years he began to lose control over his gambling. He had developed suicidal ideation. He reported a diagnosis of diabetes and restless legs syndrome and taking pramipexole (mirapex) during the past 2 years.

‹#› Medications leading to Gambling Disorder • Dopamine replacement therapy (DRT) • In the DOMINION study (n=3, 090) one or more behavioral addiction was identified in 13. 6% of patients (gambling disorder in 5%) • Hedonic homeostatic dysregulation) is a drug addiction like state marked by self medication with inappropriately high doses of dopaminergic medications, particularly L dopa and high potency, short acting dopamine agonists

‹#› Medications leading to Gambling Disorder • Several closely related phenomena have also been identified • (1) punding— repetitive, purposeless behaviors, characterized by an intense preoccupation with specific items or activities • (2) hobbyism—similar, but higher level repetitive behaviors • (3) walk abouts—consisting of excessive, aimless wandering • (4) hoarding—acquisition/inability to discard items

‹#› Medications leading to Gambling Disorder • Previous studies have demonstrated that the clinical manifestations of dopamine agonist withdrawal are similar to those found in withdrawal from other psychostimulants including psychiatric (anxiety, dysphoria, depression, agitation, irritability, suicidal ideation) and autonomic (orthostatic hypotension, diaphoresis) symptoms • No well established treatment for dopamine agonist withdrawal syndrome • Care requires close management by a neurologist/psychiatrist

‹#› Medications: Summary • Great likelihood that your patients have a comorbid psychiatric condition • Treat the comorbid psychiatric condition (with or without medications) • Naltrexone particularly for those with other addictions • If you are treating a patient with Parkinson’s Disease or Restless Legs Syndrome: call the neurologist and notify them!

‹#› References • Hollander E, Pallanti S, Allen A, et al. Does sustained release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders? Am J Psychiatry 2005; 162: 137. • Dannon PN, Lowengrub K, Gonopolski Y, et al. Topiramate versus fluvoxamine in the treatment of pathological gambling: a randomized, blind rater comparison study. Clin Neuropharmacol 2005; 28: 6. • Mc. Elroy SL, Nelson EB, Welge JA, et al. Olanzapine in the treatment of pathological gambling: a negative randomized placebo controlled trial. J Clin Psychiatry 2008; 69: 433. • Hollander E, De. Caria CM, Finkell JN, et al. A randomized double blind fluvoxamine/placebo crossover trial in pathologic gambling. Biol Psychiatry 2000; 47: 813. • Saiz Ruiz J, Blanco C, Ibáñez A, et al. Sertraline treatment of pathological gambling: a pilot study. J Clin Psychiatry 2005; 66: 28. • Zimmerman M, Breen RB, Posternak MA. An open label study of citalopram in the treatment of pathological gambling. J Clin Psychiatry 2002; 63: 44. • Gandara, JJ, Sanz, O, Gilaberte, I. Fluoxetine: open trial in pathological gambling. 152 nd Annual Meeting of the Am Psych Association 1999.

‹#› References • Samuel M, Rodriguez Oroz M, Antonini A, Brotchie JM, Ray Chaudhuri K, Brown RG, Galpern WR, Nirenberg MJ, Okun MS, Lang AE. Management of impulse control disorders in Parkinson's disease: Controversies and future approaches. Mov Disord. 2015; 30(2): 150 9. • Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol. 2010; 67(1): 58 63. • Black DW. An open label trial of bupropion in the treatment of pathologic gambling. J Clin Psychopharmacol 2004; 24: 108. • Kim SW, Grant JE. An open naltrexone treatment study in pathological gambling disorder. Int Clin Psychopharmacol 2001; 16: 285. • Kim SW, Grant JE, Adson DE, Shin YC. Double blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biol Psychiatry 2001; 49: 914. • Grant JE, Kim SW, Hartman BK. A double blind, placebo controlled study of the opiate antagonist naltrexone in the treatment of pathological gambling urges. J Clin Psychiatry 2008; 69: 783. • Grant JE, Potenza MN, Hollander E, et al. Multicenter investigation of the opioid antagonist nalmefene in the treatment of pathological gambling. Am J Psychiatry 2006; 163: 303.