Pathological gambling and primary antiphospholipid (Hughes) syndrome: a unique neuropsychiatric association

Introduction

Pathological gambling is a chronic behavioral pathology, is recurrent, has high prevalence, and has severe morbid, social and individual impacts. It has grown in importance due to the increase of legal and online gambling opportunities. ¹ Although pathological behavior associated with gambling has been recognized since antiquity, it was only taxonomically described as a specific disorder within the spectrum of impulse control disorders 30 years ago, in the third edition of the Diagnostic and Statistical Manual of Mood Disorders (DSM-III) from the American Association of Psychiatry.^1,2 Since then, studies have shown high rates of job loss, suicide attempts, and familial, conjugal, legal, and criminal problems in the lives of these patients.^{1,3– 5} The incidence of gambling is estimated at between 1% and 3% of the adult population, which is a higher incidence than other mental disorders, such as bipolar disorder and schizophrenia; it occurs more frequently among men than women.^4,5

Antiphospholipid syndrome (APS) may be associated with diverse neuropsychiatric disorders, such as mood disorders, dementia, headaches, epilepsy, chorea, multiple sclerosis, transverse myelitis, psychosis and mania. ^{6 – 8} Until recently, there have not been any reports of patients with APS who presented pathological gambling or other specific impulse control disorders.

The objective of this article is to discuss the case of the first primary APS patient with pathological gambling and to review the literature about the subject.

Clinical case

A male patient, 53 years of age, presented with superficial thrombophlebitis of the lower extremity in 1991, which occurred again in 2001 on the right side of the internal saphenous vein. After the last vascular manifestation in 2005, when he experienced total occlusion of the magna saphenous vein in the right lower extremity, which was confirmed by Doppler ultrasound, he began to be medicated continuously with warfarin, maintaining an INR count of 2–3. He presented positive lupus anticoagulant and positive IgM anticardiolipin antibody (15.9 MPL and 11.4 MPL) at two different times, with an interval of 12 weeks, with IgG anticardiolipin antibodies and negative anti-β2GP1, and was then diagnosed with primary APS (Sapporo criterion). ⁹ Other likely autoimmune pathologies were not considered because protein electrophoresis and acute phase protein were unchanged, there were no antinuclear antibodies, and rheumatoid factor and normal serum complement were present. Homocysteine, antithrombin III, C and S protein were normal. In October 1998, the patient had sought psychiatric help because of a history of pathological gambling over more than 13 years, including financial and professional loss. He did not present any associations with bipolar disorder, mania or formal cognitive changes, sensory perception or psychomotor, but did present anxiety disorder due to premature ejaculation. The patient reported that since his childhood, he had played cards with family members and friends, and that he was more anxious and restless due to the competition than other children. His parents and brothers also liked to play, but none of them became pathological gamblers. His problem began with involvement in betting on various games – cards, billiards, and dominos – after he dropped out of school and began working and earning his own money. He began playing every day after work, and while he was playing he also smoked and drank alcoholic beverages. In the previous 7 years, he had become involved in video-poker and bingo, and when the money he earned became insufficient, he began presenting anti-social behavior, committing larceny in his workplace which resulted in a legal conviction. He was then diagnosed as a pathological gambler ¹⁰ and began using clomipramine at a dose of 25–50 mg/day. His anxiety symptoms improved until January of 1999, when he stopped treatment. He returned to treatment after 22 months due to a relapse after a prolonged period of abstinence for 9 months, complaining of solitude due to marital dissolution because of his accumulated financial losses and because the excessive amount of time he spent gambling was detrimental to his family life. He accepted psychotherapy support but abandoned treatment after the third session. In 2003, he was readmitted into a walk-in support program for pathological gamblers; he presented severe depression associated with prolonged unemployment, which was manifested as ruminative guilty thinking, apathy, exacerbated sleepiness, laziness and difficulty in finding professional opportunities. He was initially treated with 20 mg/day of fluoxetine, which was progressively increased to 80 mg/day in order to control the symptoms of depression. However, from 2004, he began abusively drinking liquor during gambling relapses, which were becoming more frequent. He opted for treatment with naltrexone, in progressive doses from 50–100 mg/day with a maintenance dose of 40 mg/day of fluoxetine in order to detox from alcohol abuse, but without controlling his impulse disorder. After another 5 months, a third drug, topiramate, was added at a daily dose varying from 25–150 mg/day, in an attempt to control the intervals and frequencies of his compulsion. He continued with this three-drug regimen until September of 2009, during which time he presented periods of decreased gambling, and other periods in which he became more involved with gambling, for example, after his retirement package was invalidated in 2008 and until the money from this benefit ended. In May 2010, he decided to stop taking his psychotropic medications and was reintroduced to the use of clomipramine at 75 mg/day, naltrexone at 50 mg/day and topiramate at 100 mg/day. He is currently removed from professional activities and is in a stable phase regarding his uncontrollable gambling. He has not had any other thrombotic episode in the past 5 years while he has been on continuous appropriate anticoagulation.

Discussion

This article focuses on the first patient with primary APS associated with pathological gambling.

The spectrum of neurological symptoms of APS or Hughes syndrome has increased since its first description in 1983, ¹¹ yet the reason why the central nervous system in these patients is especially vulnerable is still unknown. Cerebral vascular disease is still the most common neuropsychiatric complication from APS, ⁶ but other diverse manifestations, such as epilepsy, dementia, cognitive defects, headaches, chorea, multiple sclerosis, transverse myelitis, idiopathic intracranial hypertension, ocular symptoms, hearing loss and other psychiatric disorders such as depression, psychosis and mania have been associated with APS. ^{6 – 8} Non-thrombotic neuropsychiatric manifestations preceding the primary APS diagnosis have also been described in both children ¹² and adults ¹³ in the literature. Although some cases present symptoms associated to some degree with underdiagnosed ischemia, other mechanisms might have caused these changes, such as inflammatory alterations or direct damage from the antiphospholipid antibodies to the neural tissue. ¹⁴

Pathological gambling had not been officially recognized as a disorder until its inclusion in the list of impulse control disorders (ICD) in the DSM-III.^1,2 It has been treated as a chronic psychiatric disorder, with a similar course of chemical dependency: intermittently, with remissions and relapses triggered by stressful stimuli, aversions or negative sentiments preceding taking advantage of gambling opportunities.^{3,15– 17} In relation to the case described here, the requirements associated with uncontrollable gambling, as recommended by the current version of the DSM-IV, were fulfilled, including anti-social behavior with criminal involvement, which is common in cases of indebtedness due to gambling. ¹⁰ These criteria do not involve suicide attempts, which have occurred in 20% of patients. ³ The patient reported here had not had any classic suicide attempts, and his excessive consumption of alcohol and tobacco were only associated with gambling. This consumption not only interfered with the most effective control of anticoagulation, but also increased his thrombogenic risk. These habits could be interpreted as an unconscious form of self-sabotaging the success of his APS treatment.s

In general, pathological gamblers who are not undergoing treatment have a high prevalence of a second ICD (23–43%), mood disorders (around 72% at least one episode of major depression during their lifetime), drug abuse (rates vary between 48% and 60%), obsessive–compulsive disorder (1–20%) and anxiety (16–40%). Bipolar disorder, mania, panic disorders, attention deficit disorder and psychosis have also been described, and there is a comparatively higher prevalence of anti-social personality disorder than in control groups.^1,18 One large epidemiological American study about alcohol use and associated conditions conducted in 10,563 individuals over the age of 60 showed that 24.74% were recreational gamblers, but that only 0.85% demonstrated pathological gambling behavior. It was noted that when comparing recreational and compulsive gamblers, there was a higher rate of alcohol consumption, nicotine use, mood changes, anxiety and personality disorders in the pathological gamblers. They also showed a higher rate of drug use and, interestingly, a previous diagnosis of arthritis (60.2% versus 44.3%) in relation to non-pathological gamblers and non-gamblers. ¹⁷ It is possible that the reduction of mobility in elderly patients with arthropathies may be one of the factors influencing an exaggerated tendency towards sedentary activities. In our case of the pathological gambler, not only did he have a major episode of depression with anxiety disorders, coupled with alcohol and nicotine use and anti-social behavior disorder, but also periods of lower mobility and functional impairment because of his repeated episodes of venous thrombosis.

The phenotypic profile and the psychiatric comorbidities of pathological gamblers may still provide insights into understanding the neurochemical mechanisms involved in this disorder. It is known that pathological gamblers tend to have reduced serotonin, dopamine, and GABA activities, and high levels of noradrenaline and glutamate, as well as an opioid system dependent on the stimulus provided by gambling, with mood dysfunction of behavioral conditioning and of motivation, a tendency towards anxiety, impulsivity and addictive behavior. ^{15 – 20}

In practice, however, what we observed in the case described here is that the same patient can alternate between distinct associated psychiatric comorbidities during the course of the disease. Consequently, intensive psychiatric observation is necessary for therapy to be adjusted to each one of these phases using non-habitual drugs in the treatment of pathological gambling. The patient in question, for example, benefited from the included use of clomipramine, which was recommended for treatment of his premature ejaculation and its anxiety component, but could even used be in the control of patients with trichotillomania, another impulse disorder.^6,18

Reviews of the treatment regimens for pathological gambling in the last decade recognize the superiority of the combination of psychotropic pharmaceuticals, cognitive behavior therapy and active participation in group therapy.^5,6,18 The patient in question was resistant to individual psychotherapy, although he regularly attended a multi-focused support group at our hospital.

It is already known that schizophrenic patients chronically treated with neuroleptics, whether phenothiazines or butyrophenones, including new drugs such as clozapine and risperidone, can have an increase in lupic anticoagulant and anticardiolipin antibody expression, increased rates of IgM without elevated IgG beta2-glycoprotein-1 or the clinical risk of thrombosis. ²¹ On the other hand, around 32% of psychotic patients left untreated pharmaceutically or those with a previous vascular event showed higher levels of lupus anticoagulant and anticardiolipin, inviting discussion about a possible role of these antibodies during psychosis. ²² The apparent increase in the cases of an association between thromboembolism and antipsychotic drugs with the use of clozapine seems to demonstrate that the pathological mechanisms involved would be indirect and more related to sedation, low level of mobility and obesity, than to the increase in the level of antiphospholipid, platelet aggregation altered by serotonin, hyperprolactinemia or hyperhomocysteinemia.^21,22

Although there is no evidence that pathological gambling is a part of the neuropsychiatric manifestations of APS, studying more cases of this association may suggest patterns of association between the presence of antiphospholipid antibodies and pro-inflammatory patterns and of neurochemical changes in the APS neuropsychiatry.