Studies have suggested that depression has a higher incidence in patients with PD [21]. Although depression is a common symptom of other diseases and usually occurs in the elderly, available evidence suggests that depression is more common in patients with PD than in the normal elderly population and those with other chronic and disabling diseases (such as osteoarthritis) [22]. Depression can occur in all stages of PD, even before tremors, bradykinesia, and other motor symptoms, suggesting that depression may be a precursor of PD [23].
In the present study, 328 patients with PD were studied in the two hospitals in Guiyang. The results showed that the prevalence of dPD was 53.4%, including mild (13.4%), moderate (31.2%), and severe (8.8%) depression. The prevalence was 65% in female patients and 44% in male patients. Foreign studies showed that the prevalence of dPD was 40–50% [9–11], consistent with the findings of this study. However, the incidence of dPD is different in different studies. Foreign studies revealed a relatively high prevalence of moderate-to-severe depression; the average prevalence of dysthymia, mild depression, and severe depression was 22.5%, 36.6%, and 24.8%, respectively[24]. Compared with foreign data, the proportion of moderate-to-severe depression in dPD in China was low. An epidemiological study by Yu et al. [25] showed that the incidence of dPD in China was 69.23%, of which mild-to-moderate depression accounted for 65.38% and severe depression accounted for only 3.85%. This might be because of the difference in the diagnostic criteria for depression, scales in the survey, and study populations [26]. Overall, the prevalence of dPD is relatively high.
At present, the most commonly used and effective drug for the treatment of PD is levodopa. However, most patients after treatment with levodopa for a period of time develop complications such as reduced efficacy, psychiatric symptoms, dyskinesia, “on–off” phenomenon, wearing-off, and so on. Moreover, levodopa is ineffective in patients with dPD. It is often administered in combination with antidepressants, leading to serious adverse reactions. DA receptor agonists can improve the sensitivity of patients to DA replacement therapy, and usually achieve better therapeutic effects in combination with levodopa. Pramipexole is a novel DA receptor agonist with high selectivity for D2 and D3 receptors, and its affinity for D3 receptors is significantly higher than that for D2 receptors [27]. It not only has a good therapeutic effect on PD-related motor symptoms but also can improve the depressive symptoms of patients and their quality of life [28]. Therefore, it may be a potential antidepressant drug [29], which is more beneficial for patients with dPD. A multicenter, parallel-controlled, and open-label study compared the effects of pramipexole and sertraline in treating PD with major depressive disorder. The results showed that both drugs could improve symptoms of dPD, but pramipexole was more effective [27].
At present, SSRIs are the most commonly used drugs for treating patients with dPD. Given their fewer adverse drug reactions and good tolerance, they are commonly used in clinical settings, especially suitable for the elderly. As shown in the survey, 62.9% of patients with dPD were administered SSRIs, 20% chose novel non-SSRI antidepressants (such as venlafaxine and mirtazapine), and only 7.4% chose TCA [30]. Although fewer case reports showed that SSRIs might aggravate motor symptoms of PD, it was not confirmed in several large-scale studies[31]. A recent double-blind, randomized, placebo-controlled trial[32] explored the efficacy of paroxetine versus venlafaxine sustained-release capsules in the treatment of dPD; 115 patients with dPD were treated for 12 weeks. The results showed that both paroxetine and venlafaxine could significantly improve the symptoms of dPD and did not aggravate the motor symptoms of PD. However, previous studies on SSRIs for the treatment of dPD focused on paroxetine, and related studies suggested insufficient evidence for the efficacy of fluoxetine, sertraline, and citalopram in treating dPD [33]. Especially for the newly marketed SSRI escitalopram, few studies reported its usage in treating dPD, which were underpowered to support its efficacy in these patients.
TMS is a novel painless, noninvasive physical therapy and technique widely used in the studies and treatments of depression. According to the frequency, it includes high-frequency rTMS (frequency > 1 Hz) and low-frequency rTMS (frequency ≤ 1 Hz). Different frequencies have different effects on brain nerve cells: high frequency leads to excitation, and low frequency produces inhibition. The left DLPFC is involved in the generation and regulation of positive emotions, and the right DLPFC participates in the generation and regulation of negative emotions. Studies have found that the left DLPFC function is abnormally decreased, while the right one is significantly increased in patients with depression. Both high-frequency rTMS stimulation of the left DLPFC and low-frequency rTMS stimulation of the right DLPFC are effective in treating depression [34].
This study compared the therapeutic effects of the conventional anti-PD therapy with escitalopram, pramipexole, and high-frequency rTMS on dPD, and found that depression in all treatment groups showed different degrees of improvement compared with that before treatment. After the conventional anti-PD therapy, the HAMD scores of the patients decreased slightly, suggesting emotional improvement in patients compared with that before treatment. It might be because of the anti-PD therapy. The physical symptoms of the patients were relieved, which alleviated their painful experience caused by the disease and increased their confidence in the treatment, thus contributing to improved emotional disorders.
The results of this study showed that compared with other therapies, pramipexole could quickly and effectively improve depression, and was also favorable for improvements in cognitive and motor symptoms. After 2 weeks of treatment, the pramipexole group had more HAMD score reductions compared with the other groups, indicating that pramipexole had a better antidepressant effect in the first 2 weeks of treatment. The reason for the shorter onset time of pramipexole might be that its targets were not limited to the nigrostriatal region, and it also had agonistic effects on DA D2 and D3 receptors in the hippocampus and amygdala, which could not only improve anxiety, depression, and other nonmotor symptoms of patients but also significantly improve the motor symptoms and quality of life of patients with PD. Furthermore, it could quickly improve motor symptoms, such as bradykinesia and limb tremor, in the early stage of drug administration [35]. The improvement in motor symptoms in the early stage of treatment could improve the quality of life and depression of patients.
This study found that escitalopram was better than pramipexole in terms of therapeutic effect after 4 weeks of treatment. By analyzing the reduction rate of HAMD, the response rate of escitalopram after 4 weeks was 93%, which was higher than 87% in the pramipexole group, 75% in the rTMS group, and 34% in the conventional treatment group, indicating that the antidepressant effect of long-term administration of escitalopram was more significant. Escitalopram was a highly selective 5-HT reuptake inhibitor that competitively inhibited the reuptake process by binding to the 5-HT reuptake pathway, thereby increasing the 5-HT concentration in the synaptic gap. It continuously stimulated the postsynaptic membrane, and finally the antidepressant effect could be achieved, which was 100 times the effect of citalopram on dextrorotatory enantiomer [36]. Therefore, it had powerful antidepressant effects.
Although single administration of pramipexole and escitalopram was effective in improving the depressive symptoms of dPD, early combination of escitalopram and pramipexole did not show a significant advantage over monotherapy [37]. Moreover, the novel antidepressant therapy TMS was more commonly used in the combination of antidepressant therapies. Studies [38] showed that rTMS combined with SSRIs could effectively improve the depressive symptoms of dPD.
This study showed that high-frequency rTMS effectively improved depressive symptoms, cognitive function, and dyskinesia in patients with dPD. However, the antidepressant effect of high-frequency rTMS was not as good as that of escitalopram and pramipexole. Previous studies showed that both high- and low-frequency rTMS had antidepressant effects, but high-frequency rTMS was more effective [39]. A study found that high-frequency TMS stimulation of the frontal lobe significantly improved the activities of daily living, motor function score, turning, and buttoning ability of patients [40], suggesting that high-frequency rTMS could also improve dyskinesia in patients with PD and facilitate recovery of motor function.. Fregni et al. [41] found that rTMS, such as fluoxetine, could increase cerebral blood perfusion in patients with PD, regulate cortical excitability, improve cerebral blood circulation, affect catecholamine metabolism in the brain, promote the release of endogenous DA, increase DA around ipsilateral caudate nucleus, inhibit the decomposition of DA in the cerebral nervous system, and regulate the excitability of the direct and indirect circuits of globus pallidus of the affected striatum.
In conclusion, escitalopram, pramipexole, and high-frequency rTMS had good effects on dPD. Escitalopram had the best antidepressant effect, while pramipexole had a faster onset time. Although high-frequency rTM was inferior to the aforementioned two drugs in terms of therapeutic effects, it might be a good auxiliary treatment as a painless and noninvasive therapeutic regimen.