Apathy in Parkinson's disease: neurophysiological evidence of impaired incentive processing.

Apathy is one of the most common and debilitating nonmotor manifestations of Parkinson's disease (PD) and is characterized by diminished motivation, decreased goal-directed behavior, and flattened affect. Despite its high prevalence, its underlying mechanisms are still poorly understood, having been associated with executive dysfunction, and impaired emotional processing and decision making. Apathy, as a syndrome, has recently been associated with reduced activation in the ventral striatum, suggesting that early- to middle-stage Parkinson's disease patients with this manifestation may have a compromised mesocorticolimbic dopaminergic pathway and impaired incentive processing. To test this hypothesis, we measured the amplitude of the feedback-related negativity, an event-related brain potential associated with performance outcome valence, following monetary gains and losses in human PD patients (12 women) and healthy controls (6 women) performing a gambling task. Early- to middle-stage PD patients presenting clinically meaningful symptoms of apathy were compared with nonapathetic PD patients and healthy controls. Patients with cognitive impairment, depression, and other psychiatric disturbances were excluded. Results showed that the amplitude of the feedback-related negativity, measured as the difference wave in the event-related brain potential between gains and losses, was significantly reduced in PD patients with apathy compared with nonapathetic patients and healthy controls. These findings indicate impaired incentive processing and suggest a compromised mesocorticolimbic pathway in cognitively intact PD patients with apathy.

Effect of CYP2D6 on risperidone pharmacokinetics and extrapyramidal symptoms in healthy volunteers: results from a pharmacogenetic clinical trial.

AIM: To elucidate the relationship between CYP2D6 genotype and risperidone pharmacokinetics and extrapyramidal symptoms we propose the APSEP pharmacogenetic clinical trial. MATERIALS & METHODS: Twenty-five healthy subjects were included in this randomized, placebo-controlled, single dose (risperidone 2.5 mg) crossover and double-blind clinical trial. Subjects were selected according to their CYP2D6 genotype and classified as: poor metabolizers (n = 8), extensive metabolizers (n = 10) and ultrarapid metabolizers (n = 7). RESULTS & CONCLUSION: Our study demonstrates that CYP2D6 predicted 65% of the risperidone metabolism variability. Moreover, its ability to predict actigraphy records is similar to the predictive power of pharmacokinetic parameters (24%). Our results also highlight the need for the development of pharmacogenetic predictors that take into account the complexity of pharmacokinetic and pharmacodynamic relationships.

Relationship between CYP2D6 genotype and haloperidol pharmacokinetics and extrapyramidal symptoms in healthy volunteers.

AIM: This study aimed to elucidate the relationship between CYP2D6 genotype and haloperidol pharmacokinetics and induced extrapyramidal symptoms (EPSs). MATERIALS & METHODS: Twenty five healthy subjects were included in this randomized, placebo-controlled, single-dose (5 mg) crossover and double-blind clinical trial, selected according to their CYP2D6 genotype and classified as poor metabolizers (n = 8), extensive metabolizers (n = 10) and ultrarapid metabolizers (n = 7). RESULTS & CONCLUSION: We confirm that CYP2D6 genotype partially determines haloperidol metabolism and the rate of EPSs measured as wakefulness activity by actigraphy. The best predictor of wakefulness activity was the model including haloperidol area under the plasma concentration-time curve, sex and tranquilization, which explained 48.3% of the total variance. However, other markers need to be identified in order to explain the observed variability of haloperidol response and to develop pharmacogenetic predictors of haloperidol-induced EPSs.