Our findings are mainly in the following aspects. First, the incidence of DDS was approximately 2.2%, and the cumulative incidence of DDS gradually increased with the extension of follow-up time. Second, hypersexuality, compulsive eating, compulsive shopping, anxiety and lower H-Y stage were independent risk factors for the development of DDS. Finally, DAT uptake values correlate with DDS occurrence. Patients taking dopamine agonists had a higher risk of developing DDS than patients taking levodopa.
Previous studies have shown a wide variation in the prevalence of DDS, ranging from 2.2% to 10.4% [5, 6, 8, 18, 19]. Accumulating evidence suggests that DDS in PD patients is the result of a history of dopaminergic drug use, genetic predisposition, history of psychiatric disorders, and impulsive personality [9, 12]. The reason why the incidence of DDS in this study was slightly lower than that in previous studies may be related to the following aspects: first, unlike this study, most patients in previous studies received dopaminergic drug treatment [6, 19]. Second, the patients included in this study were mostly Caucasian and had a shorter disease duration, whereas the patients in the study by Tsai et al. were Asian and had a longer disease duration [18, 20, 21]. Finally, it may be related to the early PD of the patients in this study. At present, there are few and different conclusions about the incidence of DDS at home and abroad, and the prevalence of DDS still needs further research.
In the past 10 years, there has been very little research on risk factors for the development of DDS. In our study, patients with impulse control disorder (ICD)-related symptoms (hypersexuality, compulsive eating and compulsive shopping) were more likely to develop DDS, which is consistent with the findings of Cilia et al. [12]. Previous studies have confirmed that the occurrence of ICD is related to the overstimulation of dopamine receptors in the mesolimbic pathway [22], and the occurrence of DDS is often accompanied by ICD [23, 24]. Therefore, our findings suggest that patients with ICD are prone to DDS, possibly due to the similar pathophysiological mechanisms of DDS and ICD [25]. In addition, in the study by Tanaka et al., patients taking levodopa were more likely to develop DDS than dopamine agonists[9]. However, our study found that patients taking dopamine agonists had a higher risk of developing DDS. Because ICD-related symptoms are an independent risk factor for DDS in the patients in this study, some studies have confirmed that the occurrence of ICD is mostly related to dopamine agonists [26]. Therefore, the reason why our results are inconsistent with previous studies may be that dopamine agonists are a confounding factor in the occurrence of DDS by affecting ICD and thus DDS.
Previous studies have established a link between depression and the occurrence of DDS [11]. However, we did not conclude that depression could independently predict the occurrence of DDS in our study. Differences in follow-up time, assessment tools, genetic background, and study population may contribute to this difference. Notably, our study found anxiety to be an independent predictor of DDS development. To our knowledge, the occurrence of DDS is associated with dopamine replacement therapy, especially levodopa. In view of the results of this study, we can make the following explanations. First, compared with PD patients, DDS patients are more prone to mood disorders, which may be related to the sensitization of the ventral striatum caused by long-term high-dose dopaminergic drugs [27]. Second, levodopa has traditionally been known to improve mood [28]. However, studies have confirmed that levodopa not only does not improve mood [29] but also aggravates mood disorders [30]. At present, the neurobiological mechanism of levodopa on the occurrence of anxiety is still unclear. Recent studies in animal models of PD suggest that levodopa may interfere with the function of the norepinephrine and serotonin systems in emotion-related brain structures [31, 32], thereby inducing the development of anxiety and depression. Finally, mood disorders in turn increase vulnerability to substance abuse risk [33]. Thus, our results suggest that the intrinsic disease process by which PD predisposes patients to mood disorders may affect dopaminergic neurotransmission, thereby increasing susceptibility to DDS. In addition, two studies have demonstrated that antipsychotics can improve some of the symptoms of DDS [34, 35], indicating that DDS and mood disorders interact and influence each other.
In addition, a novel finding of our study is that the H-Y stage is associated with the development of DDS, and interestingly, patients with H-Y stage 1 are more likely to develop DDS than PD patients with H-Y stage 2. In the study of Cilia et al.[12], there was no significant difference in H-Y staging between the two groups, which may be related to the off-stage staging of the study. To further analyze the reason why the incidence of DDS in H-Y stage 1 is higher than that in stage 2, we compared the clinical characteristics of patients with H-Y stages 1 and 2 after follow-up and found that the age, age of onset, UPDRSIII score and UPDRS total score of PD patients with H-Y stage 1 were significantly lower than those of PD patients with stage 2. Our results can be interpreted as follows. First, many studies have confirmed that PD patients with younger onset age are more likely to develop DDS [10-12]. This may be related to the fact that PD patients with younger onset age can establish comprehensive Parkinson's disease clinical manifestations faster, worsen the treatment effect of levodopa, have earlier side effects and are more prone to motor fluctuations [36]. In addition, it has been confirmed that age may significantly mediate vulnerability to drug addiction [37]. Although PD patients are mostly middle-aged and elderly, earlier exposure to addictive drugs in patients with a younger age of onset affects the subsequent development and severity of substance dependence. This result may be related to the lower age and age of onset of H-Y stage 1 patients. Second, patients with lower stages have milder symptoms and may have higher requirements for their own mobility.
Finally, many studies have confirmed that ICD is related to the function of DAT [38-41], but the relationship between the occurrence of DDS and DAT uptake is still unclear. We analyzed DAT uptake values before and after DDS in patients with early PD and found that mean DAT uptake values in the caudate and putamen were significantly lower in patients with DDS after follow-up compared with baseline. It can be speculated that the occurrence of DDS may be related to the low uptake value of DAT. Due to the lack of data on DAT uptake values after follow-up in this study, we could not explore whether DAT uptake values could predict the occurrence of DDS. In the future, the sample size can be increased to further explore the neurobiological mechanism of DAT function affecting the occurrence of DDS.
The strengths of this study include the long-term follow-up, relatively large sample size, and new-onset PD cohort study. Although some missing data in the dataset may affect the results, the regression model constructed in our statistical analysis fit well. However, this study also has certain limitations. First, the diagnosis of the above factors is only based on scale evaluation, without objective quantitative index description. Second, the data related to DAT function in this study were missing a lot, and the relationship between DAT intake value and the risk of DDS was not explored. In future research, the DAT data of PD patients will be examined, and the relationship between DAT uptake and DDS will be further explored.