Impulse control disorders in Parkinson's disease.

Since the original descriptions of hedonistic homeostatic dysregulation syndrome and pathological gambling in Parkinson's disease, impulse control disorders, such as compulsive spending, punding, or binge eating, are increasingly recognized. Although the term hedonistic homeostatic dysregulation syndrome has been supplanted by the concept of the dopamine dysregulation syndrome, the features of severe dyskinesias, cyclical mood disorder with hypomania or manic psychosis, and impairment of social and occupational functioning in the setting of increased intake of antiparkinson therapy remain. At this time, impulse control disorder is defined as maladaptive behaviors that emerge with disease progression and increasing antiparkinson medications. These behaviors may be disruptive, such as punding, or destructive, such as compulsive spending, gambling, binge eating, or hypersexuality.

Introduction and context

It has long been recognized that treatment of the motor symptoms of Parkinson's disease (PD) with dopamine replacement therapy (DRT) may be associated with psychiatric disturbances [1]. Additional behaviors, characterized by impulsivity and/or compulsivity, include pathological gambling, hypersexuality, compulsive shopping, binge eating, punding, and overuse of DRT [2-8]. In addition, overuse of DRT has been referred to as homeostatic hedonistic dysregulation (HHD) or dopamine dysregulation syndrome (DDS) [9,10]. In DDS/HHD, patients inappropriately consume more dopaminergic medication than is required to adequately control motor symptoms and often experience significant disruption of social and employment activities [11].

Whereas disruptive or compulsive behaviors appear to be linked to levodopa replacement therapy, destructive behaviors are more often associated with behavioral addiction, predominantly in PD patients using dopamine agonists [8,12]. Features associated with these behaviors include early age of onset, longer duration of disease, family history of psychiatric disorders, depression, or prior history of gambling. The majority of reports indicate that the onset of these behaviors is associated with the use of dopamine agonists either as monotherapy or in addition to levodopa rather than with the use of levodopa alone. Patients with binge eating disorder usually have other behavioral addictions, including pathological gambling, compulsive shopping, hypersexuality, and punding, as well as a history of weight control issues [5]. The abnormal behaviors of hypersexuality range from markedly increased sexual drive to rare reports of paraphilia [8]. These symptoms appear to be more common in men with early-onset PD. Unlike other destructive behaviors, hypersexuality has been associated with levodopa, dopamine agonists or selegiline, and a history of alcohol or tobacco addiction [8].

Recent advances

Phenomenology: impulse control disorders

The true prevalence of impulse control disorder (ICD) has yet to be defined, but the development of these symptoms is correlated with age, disease duration, a prior history of depression or drug abuse, and a number of other factors (Table 1). Screening of 272 consecutive PD patients revealed a prevalence rate for pathological gambling, hypersexuality, or compulsive shopping of 4% and a lifetime prevalence rate of 6.6 to 9.1% [13,14]. However, the DOMINION study (Impulse Control Disorders in Parkinson's Patients Treated With Pramipexole and Other Agents), a prospective multi-centered trial to assess the frequency of these behaviors in more than 3,000 subjects, has found that at least one ICD was identified in 13.6% of patients, while 4.9% of patients had multiple behaviors. The frequencies of single ICDs reported for the entire population were: compulsive buying (5.7%), compulsive gambling (5.0%), binge-eating disorder (4.3%), and compulsive sexual behavior (3.5%) [15].

Table 1.

Risk factors for impulse control disorders (ICD) [23]

Risk factors for ICD	Possible ICDs	Definite ICDs
Diagnosis prior to 50 years of age	Reported change in personality or behavior	Compulsive behavior (punding) >1 hour/day
Diagnosed for >5 years	Increased secrecy	Addictive behavior:
Male gender	Increased time at hobbies or work	Gambling
History of depression, anxiety, or bipolar disorder	Decreasing need for sleep or complaints of insomnia	Shopping
Prior drug/alcohol abuse	Increased medication intake	Increased libido
Prior gambling or other behavioral addiction	Hoarding medications	Hypersexual behavior
Family history of mental illness	Family history of drug/alcohol addiction	Binge eating
Dyskinesias
Levodopa or equivalent dopaminergic therapy dosages >1,000 mg/day
Dopamine agonist therapy

ICD, impulse control disorder.

Although the majority of the reports note an association of these behaviors with the use of dopamine agonists, some cases do occur in patients on levodopa alone. It has also been argued that ICD behaviors may be independent of DRT and secondary to disease severity and progression [8,13,14].

Dopamine dysregulation syndrome

Approximately 4% of PD patients on DRT are reported to overuse dopaminergic medications. Compulsive medication dosing has been noted to be more prevalent in men [14,16]. In addition, a history of alcohol abuse, mood disorders, and family history of psychiatric problems may be predisposing factors. Diagnostic criteria have been proposed for DDS and include at least a 6-month history of the need for increased doses of DRT, pathological drug use, impairment in social or employment functions, affective disorders, and a withdrawal state when medications are decreased [10,11]. Some individuals with DDS meet diagnostic criteria for substance dependence [13,14].

Punding

Punding refers to aimless repetitive activity often involving manipulations of a familiar object. The term is borrowed from the vernacular of Swedish intravenous amphetamine addicts exhibiting this behavior and is loosely translated as ‘blockhead’. This behavior was first suggested as being levodopa-induced by Dr Joseph Friedman. Now punding is defined as compulsive performance of repetitive tasks, such as assembly/disassembly, collecting things, or sorting household objects [17-19]. Other behaviors, ‘hobbyisms’, that may represent variants of punding include excessive humming or singing, inordinate writing, paper shuffling, blogging/journaling, doodling, painting, walkabouts, and reciting long meaningless soliloquies without an audience. Interestingly, performance of these behaviors may be linked to increased synaptic dopamine, since amphetamine, cocaine, and levodopa share a presynaptic mechanism. In addition, these activities seem to be more prominent during ‘on time’ and ‘on time with dyskinesias’. These repetitive behaviors are associated with high dosages of DRT (greater than 800 levodopa equivalents per day) and seem to occur in the ‘on-state’.

Pathogenesis

The anatomic substrate for ICD is not fully elucidated. The direct pathway, mediated through D1 dopamine receptors, is associated with the development of motor symptoms of PD, such as wearing off and dyskinesias. The D2 dopamine receptor mediates neuronal activity in the indirect pathway and has a prominent role in ICD in PD and in addiction disorders [8]. Within the D2-type receptor family are D3 receptors, which reside within the ventral striatum/nucleus accumbens and modulate non-motor circuits. These non-motor circuits include: the dorsolateral prefrontal cortex, regulating executive function; the lateral orbitofrontal cortex, modulating socially appropriate behavior and mood; and the anterior cingulate cortex, initiating activity and maintaining interest [20,21]. Given the homologies of binding sites between levodopa and amphetamine, receptor changes in PD may underlie the disruptive behaviors of DRT-related compulsivity, similar to punding in addiction disorders. Destructive behaviors may arise in the continuum of neurodegeneration, levodopa-related changes, and the addition of variably selective D3/D2 dopamine agonists [8].

Recent outcomes

In July 2007, the first international meeting devoted to this topic was held in Toronto [22]. Nearly 100 clinicians and researchers from six countries met in this 2-day workshop to discuss a wide range of topics, including punding, behavioral addiction, addiction to DRT, and the seemingly paradoxical observations concerning the use of deep brain stimulation in this population. The faculty for the seven scientific sessions represented subspecialty interest in neurology, psychiatry, addiction, and neuroscience, and a poster session provided additional new information concerning this interesting behavioral syndrome. The major outcomes from this meeting were: (1) defining the clinical features of this syndrome [23], and (2) identifying an unmet need for validated clinical assessments in this population of PD patients [24].

Implications for clinical practice

Treatment of ICD requires early recognition of the symptoms. Because of the potential for these addictive symptoms to rapidly escalate, adequate and consistent patient education is important, particularly when introducing a new dopaminergic therapy or increasing the dosage of a dopaminergic agent. If any symptoms of ICD are recognized, inquiry for other symptoms is important because, for instance, symptoms of hypersexuality may require treatment strategies that differ to those of compulsive spending or punding [8,25].

The initial intervention is usually a function of reducing the last medication changed in treating PD. In the initial reports of pathological gambling, the behaviors emerged after increasing dopamine agonist therapy. In the majority of these instances, reduction or discontinuation of this agent resulted in behavior benefit. In general, patients with compulsive gambling, spending, or eating usually respond to dopamine agonist reduction, whereas patients with punding benefit from levodopa reduction. The population with problems resulting from hyperhedonistic behaviors may benefit from reduction of either dopamine agonist or levodopa. Clearly, DDS requires careful reduction of dopaminergic therapy [25].

Additional treatment interventions are highly anecdotal but include treatment of comorbid depression with selective serotonin-reuptake inhibitor or other antidepressants or bipolar symptoms with lithium or antipsychotic agents, such as quetiapine or clozapine. Preliminary study with acamprosate, a synthetic structural analogue of the amino acid neurotransmitter gamma-aminobutyric acid (GABA) approved for the treatment of alcohol abuse, suggests that this agent may be helpful in treating compulsive eating and sweet craving. Counselling may be important in the setting of sexual, eating, or gambling addictions. Lay support groups for problem addictions (for example, Gamblers Anonymous) have been suggested frequently, because of additional advice regarding the financial options important in this recovery [25].