Drug-induced impulse control disorders in Parkinson’s disease

Journal of Neurology -     

Neurotrophic factors in neurodegenerative disorders: Model of parkinson’s disease

Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis--ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer's disease and peripheral neuropathy--nerve growth factor (NGF) and Parkinson's disease (PD)--glial derived neurotrophic factor (GDNF). In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OH-DA, MPTP, methamphetamine and axotomy. The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic.     

Genetics of impulse control disorders in Parkinson’s disease

Impulse control disorders (ICD) have been recognised in Parkinson’s disease (PD) as adverse effects of dopamine replacement therapy, particularly with dopamine agonists. Although virtually all PD patients are treated with dopaminergic drugs, only a minority will develop hyperdopaminergic states, suggesting predisposing and/or protecting factors. The age at onset, the sex and the dose or type of dopaminergic drugs have been identified as clinical predictive factors. Recent genetic studies have investigated associations between ICD and polymorphisms of genes involved in the dopamine metabolism pathway (COMT, DAT), dopamine receptors (DRD1, DRD2, DRD3, DRD4), serotonin receptors and its transporter (HTR2A, 5HTT), and glutamate receptors (GRIN2B). Although validation in larger and independent cohorts is needed, the results from these studies give us some insights into the pathophysiology of hyperdopaminergic states and may be useful, at term, in personalising antiparkinsonian treatment in clinical practice.     

Zonisamide in managing impulse control disorders in Parkinson’s disease

Impulse control disorders (ICDs) are a set of behaviours that take place in a subgroup of patients with Parkinson’s disease (PD). Although reduction or switch of dopamine agonists or decrease of levodopa are the common treatment, this does not always improve the compulsive behaviour. Zonisamide (ZNS) has proved effective for motor symptoms in PD and it may be also useful in the field of ICDs. The aim of our study is to evaluate the safety and efficacy of ZNS in PD patients with ICDs who did not improve following a reduction of either levodopa or dopamine agonists. Fifteen patients were initiated on 25 mg/day ZNS dosage, which was titrated to 200 mg/day, as tolerated. Severity of the behaviours was assessed by means of the Clinical Global Impression and the Barratt Impulsiveness Scale, while motor impairment was assessed by means of the Unified Parkinson's Disease Rating Scale (UPDRS). Demographic data, medication dose, treatment duration and adverse events were also collected and analyzed. There was a marked reduction in the severity of impulsive behaviours and global impulsiveness (mean change from baseline −5.8 to −4.8, respectively). UPDRS changed only marginally. ZNS was generally well tolerated. Our study suggests that ZNS may be effective for ICDs in PD. The lack of studies with other medications to treat these behaviours in PD and the potential beneficial effects of ZNS for motor complications make this drug important in the treatment of the disease.     

Impulse control disorders in Parkinson’ disease: the role of personality and cognitive status

This study reviews empirical findings on two debated issues related to the phenomenon of impulse control disorders (ICD) in patients with Parkinson’s disease (PD) treated with dopamine agonists: the role of “premorbid” or “baseline” personality traits and the role of cognitive status. A review of both these issues may help clinicians to understand why only some PD patients, when treated with dopamine agonists, develop an ICD: besides the treatment, which other neuropsychiatric characteristics represent a risk factor to develop an ICD? A literature review was performed on studies of ICD in PD patients, in electronic databases ISI Web of Knowledge, Medline and PsychInfo, conducted in January 2011. In the general population, impulsivity, depression and difficulties with executive functions, especially of inhibitory control, are factors associated with ICD development. As regards cognitive functions, PD patients present executive difficulties, and patients with ICD present more difficulties in comparison to patients without ICD. As regards personality characteristics, PD patients present a trait of negative affect, which could predispose them to affective disorders and could represent an affective risk factor for the development of ICD; as regards impulsivity, preliminary findings support the hypothesis that premorbid “baseline” levels may moderate the decrease of impulsivity because of the progressive dopaminergic deficit in PD patients and therefore also moderate the development of ICD. Longitudinal psychometric and cognitive studies, following PD patients since the clinical diagnosis and during dopaminergic treatment, are needed to confirm the role of personality traits and cognitive status on ICD development in this clinical population.     

Neuropsychiatric aspects of parkinson’s disease

Previous studies of the neuropsychiatric aspects of Parkinson’s disease were frequently methodologically inadequate. Small sample sizes, selection bias, lack of diagnostic criteria of Parkinson’s disease, different definitions and assessment of neuropsychiatric symptoms, and lack of control groups seriously questioned the validity of and ability to generalize the results from many studies. During the past decade, however, several of these methodological issues have been addressed. Recent studies have found that mild cognitive impairment is very common, and dementia, depression, and psychotic symptoms develop in a large proportion of patients. Neuropsychiatric symptoms are important determinants of mortality and disease progression, as well as of the patients quality of life and course of disease, caregiver distress, and nursing home admission. Few adequately designed treatment trials have been published, but available evidence suggests that depression and hallucinations may be effectively treated using new antidepressants and atypical antipsychotic agents without worsening of parkinsonism.     

Neuroprotection in parkinson’s disease: An elusive goal

Parkinson’s disease is a chronic progressive condition that causes disability and reduction of quality of life. Symptomatic treatments are effective in the early disease; however, with time, most patients develop motor complications. Neuroprotective therapies are those that can slow disease progression; unfortunately, these agents are not available. Advances in the knowledge of the possible pathogenic events that can lead to nigral cell death have increased dramatically. These mechanisms include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, alterations in protein degradation, and ultimately apoptosis. Based on these laboratory scientific findings, a number of agents have been studied in clinical trials. However, how to assess disease evolution and establish reliable endpoints is still an unresolved issue. The monoamine oxidase inhibitors selegiline and rasagiline have been shown to be neuroprotective in vitro and in animal models, but so far this property was not demonstrated in clinical trials. Other agents have been studied and still others are undergoing clinical investigation. These include antiexcitotoxicity drugs like riluzole, the bioenergetic agent coenzyme Q10, trophic factors, and antiapoptotic drugs. Laboratory and clinical data suggest that dopamine agonists may have a neuroprotective action, but this has yet to be proven. However, as our basic and clinical knowledge on Parkinson’s disease increases, it is likely that a neuroprotective drug will be found.     

Undetected ophthalmological disorders in Parkinson’s disease

Journal of Neurology - Ophthalmological disorders are common and frequently disabling for people with Parkinson’s disease (PD). However, details on the prevalence, severity and impact of...     

Clinical characteristics of impulse control and repetitive behavior disorders in Parkinson’s disease

Impulse control and repetitive behavior disorders (ICRBs) are a group of diseases including impulse control disorder (ICD), repetitive behavior disorder (RB), and dopamine dysregulation syndrome (DDS). This study determined the prevalence and associated characteristics of ICRBs in Parkinson’s disease (PD) patients. Included were 297 patients, interviewed with the questionnaire for impulsive-compulsive disorders in PD for screening of various ICRBs. Questionnaire results and clinical characteristics were analyzed. The ICRB prevalence among PD patients was 15.5 % (46 of 297), with 35 patients with ICD, 20 with RB, and 7 with DDS. Patients with ICRB were predominantly male, younger, taking higher doses of dopaminergic drugs, and had longer disease duration, worse Unified Parkinson’s Disease Rating Scale (UPDRS) motor score, and worse PD quality of life questionnaire score. However, each ICRB subtype had different risk factor profiles. ICD patients were predominantly male, younger, had longer disease duration, were affected by PD from young age, were taking higher total dopaminergic drug dosages, and had more RB. RB patients had higher UPDRS part III scores, were taking higher levodopa doses, and had higher comorbid ICD. DDS patients were taking higher dopamine agonist doses, and had more frequent ICD. In multivariate logistic regression for secondary analysis, only younger age and comorbid RB or DDS showed significant association with ICD and only poor UPDRS III score and comorbid ICD were significantly associated with RB. These findings suggested that different risk factors contribute to development of each ICRB subtype. ICRB could be a combination of heterogeneous disease entities that need to be treated separately.     

Imaging impulse control disorders in Parkinson’s disease and their relationship to addiction

Established substance addictions and impulse control disorders (ICDs) such as pathological gambling share similar underlying neurobiology, and recent data extends these commonalities to the risk factors that increase an individuals’ susceptibility to develop such behaviours. In Parkinson’s disease (PD), impulse control disorders (ICDs) are increasingly recognised to develop after patients begin dopamine (DA) restoration therapy, in particular DA agonists. In both the PD and non-PD population, more impulsive individuals are at increased risk for impulse control disorders. Here, we review the neuroimaging data confirming the connection between addiction and ICDs, and revealing how DA agonists might cause specific alterations of basal ganglia and cortical function that vary as a function of an individuals’ propensity for impulsivity.     

Impulse control and related behaviors after bilateral subthalamic stimulation in patients with Parkinson’s disease

The effect of subthalamic nucleus deep brain stimulation (STN DBS) on impulse control and related behaviors (ICRB) in patients with Parkinson’s disease (PD) is conflicting. We evaluated ICRB before and after bilateral STN DBS in patients with PD. A total of 89 patients with PD treated with bilateral DBS of STN underwent retrospective assessment of ICRB before and after DBS. Of the 89 patients studied, 20 patients (22.5%) had ICRB in the preoperative period. In 13 of those 20 patients (65%), preoperative ICRB improved, including resolution in six patients. Nine patients developed de novo ICRB after DBS, thus 23 patients (25.8%) had ICRB in the postoperative period. There was no demographic difference between the patients with or without ICRB in the preoperative state. In the postoperative state, the patients with ICRB had higher levodopa equivalent daily dose (LEDD) levels and lower Mini-Mental State Examination (MMSE) scores than the patients without ICRB. However, postoperative worsening or de novo ICRB did not correlate with LEDD levels or MMSE scores. Severity of ICRB worsened more after DBS in older patients. Patients with worsened or de novo ICRB after surgery had a greater decrease in Beck Depression Index scores after surgery compared with patients whose ICRB improved. In conclusion, ICRB may resolve or improve, or new ICRB may appear, after bilateral STN DBS. The difference in risk factors for preoperative vs. postoperative ICRB suggests that the pathogenesis of those conditions is different, at least in part.     

The 6-Hydroxydopamine model of parkinson’s disease

The neurotoxin 6-hydroxydopamine (6-OHDA) continues to constitute a valuable topical tool used chiefly in modeling Parkinson's disease in the rat. The classical method of intracerebral infusion of 6-OHDA involving a massive destruction of nigrostriatal dopaminergic neurons, is largely used to investigate motor and biochemical dysfunctions in Parkinson's disease. Subsequently, more subtle models of partial dopaminergic degeneration have been developed with the aim of revealing finer motor deficits. The present review will examine the main features of 6-OHDA models, namely the mechanisms of neurotoxin-induced neurodegeneration as well as several behavioural deficits and motor dysfunctions, including the priming model, modeled by this means. An overview of the most recent morphological and biochemical findings obtained with the 6-OHDA model will also be provided, particular attention being focused on the newly investigated intracellular mechanisms at the striatal level (e.g., A(2A) and NMDA receptors, PKA, CaMKII, ERK kinases, as well as immediate early genes, GAD67 and peptides). Thanks to studies performed in the 6-OHDA model, all these mechanisms have now been hypothesised to represent the site of pathological dysfunction at cellular level in Parkinson's disease.     

The putative neuroprotective role of dopamine agonists in parkinson’s disease

Parkinson's disease is probably caused by a combination of genetic and environmental factors, which trigger a cascade of events that lead to the cell death of the dopamine-containing neurons of the substantia nigra pars compacta. These processes include oxidative stress, mitochondrial dysfunction, excitotoxicity with excess of nitric oxide formation, glial and inflammatory abnormalities and apoptosis. Dopamine agonists are chemical compounds that act directly on the dopamine receptors without any previous enzymatic biotransformation. Besides their symptomatic antiparkinsonian effect, these drugs may have neuroprotective properties in Parkinson's disease through different possible mechanisms: (a) stimulation of dopamine auoreceptors, reducing thereby dopamine turnover; (b) direct antioxidant effects; (c) reduction of excitotoxicity induced by excessive subthalamic nucleus firing; (d) inhibition of mitochondrial permeability; (e) induction of trophic factors. Dopamine agonists have already shown neuroprotective effects on dopaminergic cells against a variety of neurotoxins in several in vitro and in vivo studies. Clinical studies to detect changes in the progression of the underlying neurodegenerative process in patients with Parkinson's disease treated with dopamine agonists, by assessing the dopamine terminal function in the striatum by means of PET and SPECT techniques are under way.