Literature search strategy
Data for this review were identified on searches of MEDLINE and PubMed databases from relevant articles published up until March 2007.
For the HHD section we used the following key words: ‘hedonistic homeostatic dysregulation’, ‘dopamine dysregulation syndrome’, ‘dopamine replacement therapy and reward systems’. For the pathological gambling section we used as key words ‘pathological gambling’ in combination with ‘Parkinson’s disease' and ‘dopamine replacement therapy’. For the impulsive decision making paragraph we searched: ‘impulsive decision making’, ‘gambling task’, ‘ventromedial prefrontal cortex’ in combination with ‘Parkinson’s disease'.
The same literature research criteria used for each aforementioned section were valid for the corresponding summarizing tables (Tables 1–3). Moreover, references from relevant articles were used when necessary.
Table 1. Hedonistic homeostatic dysregulation: Case reports of compulsive DRT and HHD in PD (Lawrence et al.24)
|Reference||n/Sex||Past or family history of psychiatric disorder||Previous history of substance abuse||Mean age of onset of PD (years)||Mean age of onset of compulsive DRT (years)||Daily DRT|
|Quinn et al.25||1 M|| ||–||44||47||≤4000 mg LEDD|
|Vogel and Schiffer26||1 M||Suicide by mother||–||46||49||≤2000 mg LEDD; Bromocriptine|
|Priebe27||1 F||No||No||49||60||≤5000 mg Levodopa|
|Nausieda28||5 M||No||–||50 (41–55)||54 (46–50)||1900 mg (1500– 2500 mg) LEDD|
|Tack et al.29||1 F||Schizophrenia||–||18||25||≤2500 mg LEDD|
|Uitti et al.30||1 M||No||–||37||64||750 mg LEDD|
|Soyka and Huppert31||1 M||Alcoholism||Alcoholism||44||–||≤1800 mg LEDD|
|Weinman and Ruskin32||1 M||No||No||53||63||≥3500 mg LEDD|
|Spigset and von Scheele33||2 M||No||No||55 (51–58)||59 (52–66)||1700 mg (1500– 2000 mg) levodopa|
|Courty et al.34||4 M||Depression||Alcoholism||50 (46–57)||59 (50–65)||≥1600 mg (1100– 1900 mg) LEDD; Apomorphine|
|Merims et al.35||1 M||No||–||60||78||2200 mg LEDD|
|Giovannoni et al.36||3 M, 1 F||Depression (3), panic (1)||Alcohol (1) nicotine (1)||39 (36–42)||–||†: 3175 (2125– 5550 mg) (4) ‡: 123.25 (75–170) (4); ¶: Bromocriptine (2); Pergolide (1)|
|Gschwandtner et al.37||2 M||Depression||No||51 (43–59)||56 (50–62)||1600 mg (1000– 2200 mg) levodopa (2); Ropinirole (1)|
|Serrano-Duenas38||3 M 1 F||No||–||56 (49–62)||66 (59–71)||2600 mg (2400–2900); LEDD (4), Ropinirole (4)|
|Houeto et al.39||2 M||Bipolar disorder (1)||Alcohol (1) illegal drugs (1)||45||59 (58–61)||≤1400 mg Levodopa|
|Muller et al.40||1 F||No||Nicotine||27||35||1400 mg LEDD, Ropinirole|
|Bearn et al.41||6 M 4 F||Major depression (4)||Alcohol and nicotine (5), illegal drugs (2)||45||–||1916 (600–3200) mg LEDD|
|Pezzella et al.42||5 M 2 F||Mood disorder (6), compulsive behavior (2)|| ||51.4||–||960.5 ± 282.1 (therapeutic dose) mg LEDD|
Table 2. Pathological gambling and Impulse control disorder studies
|Reference||Type of study||No. cases and prevalence||Symptoms||Therapy|
|Molina et al.43||Retrospective||12 (out of 250); 4.8%||Pathological gambling||Levodopa, no information about DA therapy|
|Seedat et al.44||Case report||1 patient||Pathological gambling and hypomania||Pergolide, selegiline|
|Driver-Dunckley et al.45||Retrospective||9 (out of 1884); 0.47%||Pathological gambling||Levodopa|
|Kurlan46||Case report||2 patients||Pathological gambling||Levodopa, pramipexole|
|Dodd et al.47||Case report||11 patients||Pathological gambling||Levodopa|
|Imamura et al.48||Case report||6 (6 of 1411); 0.42%||Pathological gambling||Levodopa (4) (average daily dose) 525 mg|
|Pramipexole (4) (average daily dose) 4.125 mg|
|Ropinirole (1) (average daily dose) 4.5 mg|
|Avanzi et al.49||Epidemiological||6 (out of 98); 6.1%||Pathological gambling||LEDD 760 ± 207.36|
|3 levodopa and dopamine agonist|
|1 dopamine agonist|
|Weintraub et al.50||Case report||11 (out of 272)- active ICD; 4.0% 18 (out of 272)- ICD anytime during PD; 6.1%||Compulsive sexual behavior, pathological gambling, compulsive buying||LEDD 925.5 ± 534.9|
Table 3. Decision making in Parkinson's disease: patients' clinical characteristics and performance in Gambling Tasks
|Reference||Gambling task||Patient characteristics||Outcome||Therapy|
|Czernecki et al.51||Iowa Gambling Task||n = 23 UPDRS on = 12.4 (2) UPDRS off = 38.7 (2.8) Age of onset = 42.6 (2.2) Average disease duration = 14.9 (1.2)||Deficit in the IGT not sensitive to l-dopa treatment||Levodopa mg/day = 1115.3 (67.4)|
|Cools et al.52||Cambridge Gambling Task||n = 12 UPDRS on = 30.9 (6.8) UPDRS off = 47.1 (7.7) Average disease duration = 6.5 (1.4)||Impulsivity in placing bets when on medication||Levodopa mg/day = 552 (60)|
|Perretta et al.53||Iowa Gambling Task||n = 32 (16 early PD: Hoehn and Yahr score < 3; 16 later PD Hoehn and Yahr score ≥ 3) UPDRS early PD = 11.3 (1.1) UPDRS later PD = 27.2 (1.3)||IGT performance impaired in both early and later PD groups||Levodopa early PD = 265.6 (33.1) Levodopa later PD = 350.0 (38.5) Ropinirole (15 patients), amantadine (7 patients), Pramipexole (3 patients), Pergolide (3 patients), Selegiline (2 patients)|
For the general overview in the introduction we further used ‘anxiety’, ‘depression’, ‘sleep disorders’, ‘apathy’, ‘anhedonia’ in Parkinson's disease.
Studies on reward pathways in PD patients submitted to deep brain stimulation were not included in this review.
Clinical manifestations Hedonistic homeostatic dysregulation
In parkinsonian patients treated with dopaminergic drugs (dopamine or dopamine agonist) behavioral disturbances have been observed. In particular, reward-seeking, compulsive or impulsive behaviors such as pathological gambling, compulsive shopping and eating, disinhibition are described.50,54 Moreover, in some patients a compulsive dopaminergic addiction has been detected, ascribable to a dopamine dysregulation syndrome.24 All these disorders, occurring in a restricted sample of the whole parkinsonian population, may be underpinned by common alterations in the reward circuitry. The present attempt is to better conceptualize them in the theoretical framework of ‘dopamine dysregulation syndromes’, considering especially the HHD syndrome36 and underlying similarities between PD patients and drug addicts. The HHD clinical syndrome in PD has been conceptualized by Giovannoni et al.36 as a disorder consequent to dopamine replacement therapy (DRT). Diagnostic criteria of HHD require the patient to be affected by PD and responsive to levodopa therapy and needing ever increasing doses of therapy in excess of the dose normally required to relieve parkinsonian symptoms (for detailed diagnostic criteria see Giovannoni et al.36). DRT (with the dopamine precursor levodopa or synthetic dopamine agonist) is the commonest treatment for the motor symptoms of PD. A few patients take their medications beyond the quantity sufficient to relieve their motor disabilities.24,36 These patients, in spite of the motor and behavioral consequences, demand ever-increasing doses of therapy, report being able to move only when clearly dyskinetic, deny symptoms and refuse to reduce daily doses.24 There are some characteristic phenomena that might occur associated with HHD such as punding (purposeless repetitive behavior) euphoria and hypomania, altered appetite, hypersexuality, pathological gambling and shopping, heightened aggression, craving, psychosis.24 Compulsive DRT use may become evident only when attempts are made to restrict the supply of DRT (e.g. during hospitalization) when additional doses are demanded or when exaggerated ‘off’ state occurs.
The major theories of psychostimulant addiction may help to explain manifestations seen in the dopamine dysregulation syndrome (for a complete review see Lawrence et al.24). Although the syndrome can partly be explained by psychostimulants addiction theories, HHD has lately received particular attention.36
The HHD theory suggests that addicts are pushed to take drugs not only for pleasure but also to avoid unpleasant withdrawal symptoms. Hence the drug activates a pleasant state through brain reward-related circuits, which, in turn, trigger the opposite unpleasant process, so that the homeostasis could be restored. The former activation (‘a’ process) causes euphoria, the latter (‘b’ process) its decay. After repeated use the b process is strengthened and manifests as tolerance to euphoria. When the pleasant effect of the drugs wears off, unpleasant withdrawal is initiated and lasts longer than the previous one. Because only the b process is thought to grow in magnitude and duration, even a small dose of drug will reinstate it and trigger withdrawal.55 Abstinence from the drug decays the b process and, once returned to normal, the individual is no longer addicted.
Koob and Le Moal proposed an allostatic rather than homeostatic version of HHD.56 In HHD the experience of drug-induced pleasure motivates the individual, and addiction is defined as the presence of unpleasant emotional states, such as dysphoria, irritability and anxiety during abstinence.57 With repeated use of a substance, the b process, namely the process that causes the decay of euphoria, does not return to the baseline homeostatic normal state and often leads to psychiatric symptoms such as anhedonia. This state reflects a decreased baseline pleasure function, associated with reduced dopamine; pharmacological treatment augmenting dopamine release in limbic regions seems to alleviate such symptoms.58 Because baseline pleasure functions are lowered, an increase of drug intake is therefore needed to compensate for the shift in baseline reward. The altered reward-related brain activity found in some patients with PD20 may lead to increased vulnerability to DRT addiction.56,57 Hitherto the prevalence of HHD in PD has been estimated at around 4% (3.4–4%); and the disturbance seems to occur more frequently in men who have early onset of the disease and previous psychiatric history.36,42 In Table 1 recent studies on HHD are summarized.
The affective and behavioral changes seen in the HHD syndrome are similar to those found for other psychostimulants such as cocaine and amphetamines. It is likely that these similar effects are all mediated by the mesolimbic dopaminergic projections to the nucleus accumbens.36 It remains still unclear, however, why some patients develop the disorder and others do not. The hypothesis has been put forward that a previous psychiatric history, a personality disorder, temperament characteristics or familiarity for psychiatric diseases may predispose to addiction.29,33 Also, pathological changes to mesolimbic and mesocortical systems in PD may modulate the addictive potential of DRT. As previously seen, imaging studies have shown how the reward system could be dysfunctional in PD.59,60 Progressive dopaminergic denervation will reduce presynaptic dopamine storage mechanisms, triggering the pulsatile effects of DRT on limbic structures. Upregulation or changes in the sensitivity of dopamine receptors may also contribute to the development of HHD.36 An important role may also be played by the ascending dopaminergic and serotonergic projections. In particular D3 receptors are primarily localized in limbic regions in mammals and they may be involved in drug-induced reward.61 All the abused drugs such as alcohol, heroin, cocaine, tetrahydrocannabinol and nicotine increase dopamine levels in the shell of the nucleus accumbens,62 where the D3 receptors are expressed, and D3 antagonist may prove effective to manage drug dependence and addiction.61 Intracranial drug reward involves dopaminergic projections in the medial forebrain bundle63 ascending from the ventral tegmental area (VTA) to nucleus accumbens. D1 dopamine antagonist in VTA decrease the rewarding effect of cocaine; amphetamine reward is antagonized by either D1 or D2 dopamine antagonists.64 Studies suggest a more complex role of DA subtype receptors in reward, in particular a greater role for D1.65 Serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. The 5-HT2 receptor family is densely localized in the substantia nigra and VTA, as well as their terminal regions. Modulation of 5-HT2 receptor function is thought to be important in motor activation, motivation and reward; electrophysiological and biochemical data have shown that 5-HT2C receptor agonists decrease, while 5-HT2C antagonists enhance mesocorticolimbic DA function.66
Hence, the HHD theory constitutes a useful framework to conceptualize some peculiar neuropsychiatric complications of PD, underpinned by biological predisposition, neurotransmitters interactions, progression of the disease and likely to be triggered by dopaminergic therapy.
Pathological gambling and other impulse control disorders
Pathological gambling and other impulse control disorders such as compulsive buying and hypersexuality may occur in PD either as symptoms of a syndrome such as HHD or as isolated disorders. We have previously discussed HHD both as a clinical syndrome and a theoretical framework, which is useful to interpret some of the neuropsychiatric complications in PD. We will now analyze pathological gambling as an isolated disorder, with regard to its everyday life implication and relationship with DRT.
Pathological gambling is a psychiatric disorder characterized by inappropriate, persistent and maladaptive gambling behavior that has repercussions on family, personal and professional life. It is classified as an impulse control disorder67 and widely considered as a non-pharmacological addiction.68 The term ‘behavioral addiction’ has been recently used to define compulsive non-drug behaviors, assuming that they lead to similar changes in reward circuits.69,70 Other impulse control disorders usually detected in PD patients are compulsive buying and sexual behavior.25,26,30,32,34,42,50,71 Two retrospective studies, investigating the prevalence of pathological gambling in a population affected by PD, found a rate of 4.8% (12/250) and 0.47% (9/1884), respectively.43,45 An epidemiological study carried out in Italy found a prevalence rate of 0.4%.49 The authors examined a PD population on DRT therapy, ascertaining a rate of pathological gambling of 6.1% (the prevalence in the sex-matched control group was 0.25%);48 Voon et al., using the South Oaks Gambling Scale, noted that lifetime prevalence of pathological gambling was 3.4% and on any dopamine agonist, 7.2%.72
A role of dopamine therapy has been hypothesized also by Weintraub et al., who described 18 patients (6.6% of their sample) who fulfilled criteria for an impulse control disorder (ICD) at some point during the illness (compulsive gambling and compulsive sexual behavior were found to be equally common).50 Predictive elements of an ICD were treatment with a dopamine agonist and a history of ICD symptomatology prior to PD onset. There were no differences between the dopamine agonists in association with ICD, and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD.
Between 2002 and 2004 Dodd et al. identified 11 patients with PD and pathological gambling; nine of them were taking pramipexole and two, vopinirole.47 In the Molina et al. study 10 out of the 12 pathological gamblers started gambling after the onset of disease and DRT. The pathological behavior was manifest in 11 of 12 patients when they were in the ‘on’ state.43 In their retrospective review Driver-Dunckley et al. associated pathological gambling and dopaminergic therapy with dopamine agonists: eight (1.5%) of 529 were receiving pramipexole, one (0.3%) of 331 was under pergolide and none of 421 patients receiving ropinirole had pathological gambling.45 But the total number of patients exposed to pramipexole or ropinirole was not mentioned by the authors45 and the exact incidence of gambling cannot be estimated.54 But the patients with pathological gambling in the Dodd et al. study were taking high doses of pramipexole (4.5–13.5 mg/day); hence the dose of agonist might play an important part in triggering the adverse effect.
Imamura et al. noted that pramipexole and cabergoline are more selective than ropinirole for D3 receptors than D2 receptors,48 with pramipexole exhibiting a stronger effect.73 A functional magnetic resonance imaging study carried out by Reuter et al. suggested that pathological gambling was linked to a reduced activation of the mesolimbic reward system, in particular pathological gamblers showed reduced activation of the ventral striatum and ventromedial prefrontal cortex.74 It is possible that because combined therapy of levodopa and dopamine agonist may underlie a greater risk for the development of pathological gambling, patients with advanced PD and greater need for combination therapy may have an increased propensity for the disease.48 In Table 2, recent studies on the subject have been summarized. Noteworthy, all patients developing pathological gambling were on high-dose therapy. As noted by numerous authors, reducing the dose was in most cases sufficient to ameliorate pathological gambling.45,47,48
Experimental studies Impulsive decision making
Impulsive decision making is a condition of intolerance to delay of reward;73–77 it is exemplified by the reduced ability of an individual to choose a large delayed reward over small immediate ones. This behavior is observed in populations of drug addicts,78–82 although it is still unclear whether impulsivity is the cause or consequence of drug abuse.83 In this article we describe impulsive decision making because it has been frequently reported in PD patients probably due to an impairment of the mesocortical reward pathway. The condition of aversion to delay of reward can be often observed in experimental gambling tasks, but it is worth considering the clinical implications in ecologic decision-making. Furthermore, the relationship between poor decision-making and addiction in general has been emphasized.84 When a choice has to be made, information about expected outcomes has to be maintained in memory so that it can be compared and integrated with information about internal states and current goals.85 Such an integrative process generates an outcome expectancy, namely an internal representation of the consequences likely to follow a specific act.85 The orbitofrontal cortex (OFC) plays a crucial role in the generation and use of these outcome expectancies: impairments of this area lead to poor decision making,86 reversal deficits,87–90 and inability to guide behavior appropriately on the basis of the consequences of actions.91 In particular, Bechara et al. created the Iowa Gambling Task (IGT) to assess lesions to the OFC.91 In this task subjects must choose from decks of cards with varying rewards and penalties. In order to earn points the subject must be able to integrate the value of rewards and penalties. Larger rewards are associated with larger penalties. Hence, when subjects without impairments of the OFC begin to lose more than they earn, they change their strategy and turn to safer decks of cards. Individual with OFC damage instead fail to modify their responses. Czernecki et al. used the IGT in a PD population at an advanced stage of the disease and demonstrated deficits in performance, which did not change between the on medication and off medication conditions.51 Similar impairments have been also described in PD patients at earlier stages of illness.53 In order to assess the degree to which deficits in decision making are sensitive to the quality of information available, Rogers et al. introduced a novel decision-making task with contingencies presented in a readily comprehensible visual format.86 In this task boxes of two different colors were displayed at the top of a screen varying in ratio. The subject had to select where a yellow token was hidden and place a bet on their decision. Because the ratio of blue/red boxes varied from 9:1 to 1:9 there were conditions that were more and also less favorable. A normal betting strategy required a subject to select the color most likely to hide the token and modulate the amount of points to bet on the choice. To assess impulsivity two different conditions were set: in one case points to be bet increased as a function of time, in the other they decreased. An impulsive subjects do not modulate their choices but tend always to select the first conditions.52,86
It has been demonstrated that a group of PD patients was able to choose the most likely outcome, but tended when ‘on medication’ (l-dopa) to place impulsive bets, that is, to select the first choices in both the ascending and descending conditions.52 The orbitofrontal loop in mild PD is hypothesized to operate at a higher level of basal DA modulation, and so be more potentially subject to deleterious overdosing by additional levodopa-dopa medication.92 In PD subjects dopaminergic treatment causes an optimal performance in dorsolateral loop, but the same level of dopaminergic stimulation causes a decrease of performance in the orbitofrontal loop for an ‘overdosing effect’. Hence, dopaminergic therapy may help to ameliorate some cognitive skills related to the dorsolateral circuits, but has a detrimental effect on other components such as the ability to refrain from making impulsive choices. This ability is preserved when the patient is unmedicated (‘off’ state).52 Recent studies suggested a specific interaction of the ascending 5-HT system with the OFC,93,94 and one interesting speculation is that 5-HT mechanisms may contribute to different aspects of response inhibition,93 reward95 and the monitoring of negative feedback.96