Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson's Disease.

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

Treating activated regulatory T cells with pramipexole protects human dopaminergic neurons from 6-OHDA-induced degeneration.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells. METHODS: Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28-activated and non-activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co-cultured with in vitro-differentiated human dopaminergic neurons in a cytotoxicity assay with 6-hydroxydopamine (6-OHDA). The role of interleukin-10 (IL-10) was investigated by co-culturing activated IL-10-producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole-treated, CD3/CD28-activated Treg cells was determined by Fluidigm analysis. RESULTS: Pramipexole-treated CD3/CD28-activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6-OHDA. Pramipexole-treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL-10 release and the activation of genes associated with regulation and neuroprotection. CONCLUSION: Anti-CD3/CD28-activated Treg cells protect dopaminergic neurons against 6-OHDA-induced damage. In addition, activated, IL-10-producing, pramipexole-treated Tregs also induced a neuroprotective effect, and the supernatants of these co-cultures promoted axonal growth. Pramipexole-treated, activated Tregs altered their gene expression in a concentration-dependent manner, and enhanced TGFß-related dopamine receptor regulation and immune-related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD.

Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions.

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.

Dopamine agonists in restless leg syndrome treatment and their effects on sleep parameters: A systematic review and meta-analysis.

BACKGROUND: Dopamine agonists (DAs) constitute the standard therapeutic scheme for restless leg syndrome (RLS) because they have been proven to be effective. However, DAs may change sleep parameters, thus having adverse effects on patient condition. This meta-analysis clarified the effects of DAs used in RLS treatment on the sleep architecture. METHODS: PubMed, Embase, and Cochrane Central databases were searched for randomized control trials (RCT) (up to October 2023) that discussed the effects of DAs on sleep architecture in patients with RLS. A meta-analysis employing a random-effects model was conducted. The patients were divided into subgroups according to individual DAs and treatment duration (1 day or ≥4 weeks). RESULTS: Thirteen eligible randomized placebo-controlled trials were included in the assessment. The effects of three DAs (i.e., pramipexole, ropinirole, and rotigotine) on rapid eye movement (REM) sleep, slow-wave sleep (SWS), and sleep efficiency (SE) were analyzed. Overall, pramipexole significantly improved SE but decreased the percentage of REM sleep among treated patients. Ropinirole also enhanced SE compared with the placebo group. Rotigotine did not affect SE and REM sleep. Subgroup analysis found that pramipexole used for 1 day and ≥4 weeks significantly diminished the percentage of REM sleep. Ropinirole used for 1 day showed similar REM sleep patterns. Finally, none of the three DAs affected SWS. CONCLUSIONS: This meta-analysis demonstrated that DAs significantly affect sleep parameters.

Suspected duloxetine-induced restless legs syndrome phenotypic variant: a case report.

BACKGROUND: Restless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific diagnostic criteria. When effective therapeutic agents induced RAS and symptoms persisted after briefly observation, clinicians will face the challenge of weighing efficacy against side effects. CASE PRESENTATION: A 67-year-old woman was admitted to a geriatric psychiatric ward with depression. Upon admission, the escitalopram dose was reduced from 15 mg to 10 mg per day, and the duloxetine dose was increased from 60 mg to 80 mg per day. The next night before bedtime, she developed itching and creeping sensations deep inside bilateral shoulders and arms, with the urge to move, worsening at rest, and alleviation after hammering. The symptoms persisted when escitalopram was discontinued. A history of RLS was confirmed. Treatment with 40 mg of duloxetine and 0.125 mg of pramipexole significantly improved depression, and the paresthesia disappeared, with no recurrence occurring 6 months after discharge. DISCUSSION AND CONCLUSIONS: This case suggests that psychiatrists should pay attention to RLS variants when increasing doses of duloxetine. Long-term improvement can be achieved through dosage reduction combined with dopaminergic drugs instead of immediate discontinuation.

Transdermal Delivery of Pramipexole Using Microneedle Technology for the Potential Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.

Pramipexole improves depression-like behavior in diabetes mellitus with depression rats by inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing impaired neuroplasticity.

BACKGROUND: Diabetes mellitus (DM) is frequently associated with the occurrence and development of depression, and the co-occurrence of diabetes mellitus with depression (DD) may further reduce patients' quality of life. Recent research indicates that dopamine receptors (DRs) play a crucial role in immune and metabolic regulation. Pramipexole (PPX), a D2/3R agonist, has demonstrated promising neuroprotective and immunomodulatory effects. Nevertheless, the therapeutic effects and mechanisms of action of PPX on DM-induced depression are not clear at present. METHODS: Depression, DM, and DD were induced in a rat model through a combination of a high-fat diet (HFD) supplemented with streptozotocin (STZ) and chronic unpredictable mild stress (CUMS) combined with solitary cage rearing. The pathogenesis of DD and the neuroprotective effects of DRs agonists were investigated using behavioral assays, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, Nissl staining, Western blotting (WB) and immunofluorescence (IF). RESULTS: DD rats exhibited more severe dopaminergic, neuroinflammatory, and neuroplastic impairments and more pronounced depressive behaviors than rats with depression alone or DM. Our findings suggest that DRs agonists have significant therapeutic effects on DD rats and that PPX improved neuroplasticity and decreased neuroinflammation in the hippocampus of DD rats while also promoting DG cell growth and differentiation, ultimately mitigating depression-like behaviors. LIMITATION: Our study is based on a rat model. Further evidence is needed to determine whether the therapeutic effects of PPX apply to patients suffering from DD. CONCLUSIONS: Neuroinflammation mediated by damage to the dopaminergic system is one of the key pathogenic mechanisms of DD. We provide evidence that PPX has a neuroprotective effect on the hippocampus in DD rats and the mechanism may involve the inhibition of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation by DRs to attenuate the neuroinflammatory response and neuroplasticity damage.

Effects of supplementary Da Dingfeng Zhu therapy on patients with Parkinson's disease of liver-kidney yin deficiency pattern.

BACKGROUND: This study aimed to verify whether the combined use of Da Dingfengzhu and Western medicine in treating Parkinson's disease (PD) can lead to therapeutic efficacy and symptom alleviation, thereby achieving a complementary and synergistic effect. METHODS: In this study, 158 patients were initially enrolled, with 116 eligible patients randomly divided into a control and an observation group. The control group received levodopa/benserazide and pramipexole, while the observation group received Da Dingfengzhu combined with levodopa/benserazide and pramipexole for 12 weeks. Baseline patient characteristics, adverse reactions, and blood samples were collected at baseline and 12 weeks post-treatment. The Unified Parkinson's Disease Rating Scale (UPDRS) was used to assess symptom severity at baseline, four weeks into treatment, and 12 weeks post-treatment. RESULTS: Adverse reactions during treatment were similar in both groups, suggesting that the combined therapy in the observation group did not increase adverse effects. Both groups showed improvements in UPDRS scores, with the observation group displaying more significant symptom alleviation at 4 and 12 weeks. Moreover, the observation group exhibited more pronounced increases in serum neurotrophic factor-3 and dopamine levels and greater reductions in oxidative stress and inflammatory response markers. CONCLUSION: In conclusion, the combination of Da Dingfengzhu with levodopa/benserazide and pramipexole for treating PD shows significant clinical potential and is worthy of broader application.

The effects of pramipexole on motivational vigour during a saccade task: a placebo-controlled study in healthy adults.

Motivation allows us to energise actions when we expect reward and is reduced in depression. This effect, termed motivational vigour, has been proposed to rely on central dopamine, with dopaminergic agents showing promise in the treatment of depression. This suggests that dopaminergic agents might act to reduce depression by increasing the effects of reward or by helping energise actions. The aim of the current study was to investigate whether the dopamine agonist pramipexole enhanced motivational vigour during a rewarded saccade task. In addition, we asked whether the effects of pramipexole on vigour differ between reward contingent on performance and guaranteed reward. Healthy adult participants were randomised to receive either pramipexole (n = 19) or placebo (controls n = 18) for 18 days. The vigour of saccades was measured twice, once before the administration of study medication (Time 1) and after taking it for 12-15 days (Time 2). To separate motivation by contingency vs. reward, saccadic vigour was separately measured when (1) rewards were contingent on performance (2) delivered randomly with matched frequency, (3) when reward was guaranteed, (4) when reward was not present at all. Motivation increased response vigour, as expected. Relative to placebo, pramipexole also increased response vigour. However, there was no interaction, meaning that the effects of reward were not modulated by drug, and there was no differential drug effect on contingent vs. guaranteed rewards. The effect of pramipexole on vigour could not be explained by a speed/accuracy trade-off, nor by autonomic arousal as indexed by pupillary dilation. Chronic D2 stimulation increases general vigour, energising movements in healthy adults irrespective of extrinsic reward.

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks.

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modeling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

Sex differences in risk-based decision-making and the modulation of risk preference by dopamine-2 like receptors in rats.

Heightened risk-based decision-making is observed across several neuropsychiatric disorders including schizophrenia, bipolar disorder, and Parkinson's disease, yet no treatments exist that effectively normalize this aberrant behavior. Preclinical risk-based decision-making paradigms have identified the important modulatory roles of dopamine and sex in the performance of such tasks, though specific task parameters may alter such effects (e.g., punishment and reward values). Previous work has highlighted the role of dopamine 2-like receptors (D2R) during performance of the Risk Preference Task (RPT) in male rats, however sex was not considered as a factor in this study, nor were treatments identified that reduced risk preference. Here, we utilized the RPT to determine sex-dependent differences in baseline performance and impact of the D2R receptor agonist pramipexole (PPX), and antagonist sulpiride (SUL) on behavioral performance. Female rats exhibited heightened risk-preference during baseline testing. Consistent with human studies, PPX increased risk-preference across sex, though the effects of PPX were more pronounced in female animals. Importantly, SUL reduced risk-preference in these rats across sexes. Thus, under the task specifications of the RPT that does not include punishment, female rats were more risk-preferring and required higher PPX doses to promote risky choices compared to males. Furthermore, blockade of D2R receptors may reduce risk-preference of rats, though further studies are required.

Pramipexole protects against diabetic neuropathy: Effect on oxidative stress, TLR4/IRAK-1/TRAF-6/NF-κB and downstream inflammatory mediators.

BACKGROUND: Diabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN. METHODS: Sprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators. RESULTS: PPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1ß and ICAM-1). CONCLUSION: Collectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation.

Impulse control disorders in Parkinson's disease: a retrospective analysis of 1824 patients in a 12-year period.

OBJECTIVE: This study aims to clinically evaluate the impulse control disorders (ICDs) encountered in treating Parkinson's disease. METHOD: This is a retrospective analysis between 2010 and 2022. We retrieved the medical records of all patients diagnosed with idiopathic Parkinson's disease. The demographic and clinical findings were recorded. ICDs constituted a specific item in the examination, and each one (compulsive shopping, compulsive eating, pathological gambling, hypersexuality, punding, dopamine dysregulation syndrome, and hobbyism) was noted separately. RESULTS: In the study period, we identified 1824 patients (56.2% men, n = 1025). The mean age was 70.5 ± 11.9 years. In the cohort, 128 (7%) patients with Parkinson's disease had one or more ICDs. The ICDs were compulsive shopping, punding/hobbyism, compulsive eating, hypersexuality, pathological gambling, and dopamine dysregulation syndrome. When we compared patients with and without ICDs, patients with ICDs were younger (p ≤ 0.001), and the men/women ratio was higher in this group with ICDs. Although the mean daily pramipexole dose was higher in patients with ICDs, mean daily long-acting pramipexole dose was only 1.4 ± 0.92 mg/day. CONCLUSION: The significant findings in this study were (i) the lower frequency of ICDs (7%); (ii) the common occurrence of compulsive shopping, punding/hobbyism, and compulsive eating; and (iii) the development of ICDs under relatively lower doses of pramipexole. We suggest that ICDs in Parkinson's disease should be associated with a personal trait with dopamine agonists, and potential electrophysiological or genetic markers of this trait warrant further analysis to avoid treatment in these patients.

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low-Dose Extended-Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended-Release Pramipexole in Early Parkinson's Disease.

BACKGROUND: There remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity. OBJECTIVES: The objective was to determine if P2B001 (a fixed, low-dose, extended-release [ER] combination of pramipexole 0.6 mg and rasagiline 0.75 mg) is superior to each of its components and compare its safety and efficacy to optimized treatment with marketed doses of pramipexole-ER. METHODS: This was a 12-week, double-blind study (NCT03329508). Total of 544 untreated patients with PD were randomized (2:2:2:1) to treatment with P2B001, its individual components (pramipexole-ER 0.6 mg or rasagiline-ER 0.75 mg), or commercial doses of pramipexole-ER titrated to optimal dose (1.5-4.5 mg). The primary endpoint was change from baseline to week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. The key secondary endpoint was the change from baseline in the Epworth Sleepiness Scale (ESS) for P2B001 versus the titrated dose of pramipexole-ER. RESULTS: P2B001 provided superior efficacy compared to each of its components; mean (95% CI) treatment differences in UPDRS II + III scores were -2.66 (95% CI, -4.33 to -1.00) versus pramipexole-ER 0.6 mg (P = 0.0018) and - 3.30 (95% CI, -4.96 to -1.63) versus rasagiline-ER 0.75 mg (P < 0.0001). P2B001 had comparable efficacy with the titrated dose of pramipexole-ER (mean, 3.2 mg), but significantly less worsening in daytime-sleepiness (ESS treatment difference: -2.66 [95% CI, -3.50 to -1.81]; P < 0.0001). P2B001 was well-tolerated with fewer sleep-related and dopaminergic adverse events than titrated doses of pramipexole-ER including somnolence, orthostatic hypotension, and neuropsychiatric side effects. CONCLUSIONS: P2B001 had superior efficacy to its individual components and was comparable with commercially used doses of pramipexole-ER with less worsening of sleepiness and fewer dopaminergic adverse events. These findings support considering once-daily P2B001 as initial therapy for patients with early PD. © 2023 International Parkinson and Movement Disorder Society.

Dopamine agonist serum concentrations and impulse control disorders in Parkinson's disease.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) are common among Parkinson's disease patients using dopamine agonists. We wanted to determine whether ICD patients have higher dopamine agonist serum concentrations than those without any sign of ICD. METHODS: Patients who used either pramipexole or ropinirole depot once daily were screened for ICDs using the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale. Those who scored above the cut-off for one or more of the four defined ICDs (gambling, compulsive sexual behavior, compulsive shopping, and binge-eating) were compared in a case-control study to patients who scored zero points (no evidence of ICD) on the same items. They were examined clinically and evaluated using relevant scales. Three blood samples were taken on the same day: before daily dose, and then 6 and 12 h later. RESULTS: Forty-six patients were included: 19 ICD-positive and 27 controls. Ropinirole serum concentrations 6 h after daily intake (Cmax ) were higher in the case group compared to the control group, as was the daily ropinirole dosage. No differences were observed in serum concentrations, dosage or total drug exposure for pramipexole. Disease duration and length of dopamine agonist treatment was significantly longer among ICD patients for ropinirole, but not for pramipexole. CONCLUSIONS: The use of pramipexole may in itself confer high ICD risk, whereas ICDs among ropinirole users depend more on serum concentration and drug exposure. The pharmacokinetic properties of ropinirole make it challenging to predict its effects on patients, which supports the need for therapeutic drug monitoring to reduce risk of ICD.

Comparison of the effectiveness, safety, and costs of anti-Parkinson drugs: A multiple-center retrospective study.

AIMS: This study aimed to systematically compare the effectiveness, safety, and costs of different anti-Parkinson drugs (APDs). METHODS: This is a multi-center study that retrospectively analyzed the data of 8420 outpatients with PD from 2014 to 2019 across 30 tertiary hospitals in China. The effectiveness was evaluated by changes in total dosages of APDs, normalized by levodopa equivalent dose (LED) and presented as ΔLEDs; levodopa equivalent dose cost (LEDc) represented the daily cost of APDs; and newly added diagnostics were represented as APDs-related adverse events. RESULTS: A total of 384 patients with eligible medical records for three consecutive years were enrolled. Patients treated with carbidopa/levodopa or levodopa/benserazide had significantly lower mean ΔLEDs than other groups (p < 0.01), followed by pramipexole and selegiline. The piribedil group had the highest ΔLEDs, with mean differences of 112.56-355.04 mg compared to other groups (p < 0.01). Meanwhile, LEDc in the levodopa/benserazide, carbidopa/levodopa, and piribedil groups were significantly lower than those in pramipexole or selegiline groups ($0.088-0.135/day for levodopa/benserazide; $0.070-0.126/day for carbidopa/levodopa; $0.112-0.138/day for piribedil; $0.290-0.332/day for pramipexole; $0.229-0.544/day for selegiline; p < 0.01). Patients with piribedil had more adverse events, with an incidence rate of 35.7%, followed by levodopa/benserazide (25.6%), selegiline (23.5%), carbidopa/levodopa (23.3%), and pramipexole (16.4%). Pramipexole showed a lower incidence rate of adverse events than piribedil, including neuropsychiatric symptoms (p = 0.006), headache/dizziness (p = 0.016), and gastrointestinal symptoms (p = 0.031). CONCLUSIONS: Carbidopa/levodopa or levodopa/benserazide might exhibit better clinical improvement with less medical cost, while piribedil presented less clinical improvement but a higher risk of headache/dizziness, gastrointestinal, and neuropsychiatric symptoms.

Impulse control disorders in Parkinson's disease patients treated with pramipexole and ropinirole: a systematic review and meta-analysis.

BACKGROUND: This analysis is the first systematic review and meta-analysis assessing occurrences of ICD in PD patients treated with oral DAs: ropinirole (ROP) and pramipexole (PRX). This study compares the two oral DAs to a transdermal patch, rotigotine (RTG). METHODS: We performed an extensive systematic search for eligible studies from PubMed, Embase, Cochrane Library, and Google Scholar. The data was analyzed by various software, including EndNote, Rayyan, PRISM, and RevMan. Two studies incorporating 658 patients collectively were assessed. RESULTS: This meta-analysis shows a significant correlation between the usage of PRX (25.3%) or ROP (21.8%) and the development of ICD in PD patients. Compared to the transdermal patch, RTG, PRX was found to have a significant relative risk (P < 0.0001) of 3.46 (95% CI 2.07-5.76), and ROP was found to have a significant relative risk (P < 0.0001) of 2.98 (95% CI 1.77-5.02). The data collected shows RTG is approximately three times less likely to cause ICDs than oral PRX and ROP. CONCLUSION: The present investigation provides insight into ICD occurrences with PRX, ROP, and RTG to allow physicians to make more informed decisions on risk versus reward when deciding how to treat a PD patient with these drugs. However, related to various disclosed limitations, our conclusion cannot provide definitive practice protocols.

Pramipexole Enhances Reward Learning by Preserving Value Estimates.

BACKGROUND: Dopamine D2-like agonists show promise as treatments for depression. They are thought to act by enhancing reward learning; however, the mechanisms by which they achieve this are not clear. Reinforcement learning accounts describe 3 distinct candidate mechanisms: increased reward sensitivity, increased inverse decision-temperature, and decreased value decay. As these mechanisms produce equivalent effects on behavior, arbitrating between them requires measurement of how expectations and prediction errors are altered. We characterized the effects of 2 weeks of the D2-like agonist pramipexole on reward learning and used functional magnetic resonance imaging measures of expectation and prediction error to assess which of these 3 mechanistic processes were responsible for the behavioral effects. METHODS: Forty healthy volunteers (50% female) were randomized to 2 weeks of pramipexole (titrated to 1 mg/day) or placebo in a double-blind, between-subject design. Participants completed a probabilistic instrumental learning task before and after the pharmacological intervention, with functional magnetic resonance imaging data collected at the second visit. Asymptotic choice accuracy and a reinforcement learning model were used to assess reward learning. RESULTS: Pramipexole increased choice accuracy in the reward condition with no effect on losses. Participants who received pramipexole had increased blood oxygen level-dependent response in the orbital frontal cortex during the expectation of win trials but decreased blood oxygen level-dependent response to reward prediction errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning. CONCLUSIONS: The D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible mechanism for pramipexole's antidepressant effect.

Add-on pramipexole for anhedonic depression: study protocol for a randomised controlled trial and open-label follow-up in Lund, Sweden.

INTRODUCTION: Many depressed patients do not achieve remission with available treatments. Anhedonia is a common residual symptom associated with treatment resistance as well as low function and quality of life. There are currently no specific and effective treatments for anhedonia. Some trials have shown that dopamine agonist pramipexole is efficacious for treating depression, but more data is needed before it could become ready for clinical prime time. Given its mechanism of action, pramipexole might be a useful treatment for a depression subtype characterised by significant anhedonia and lack of motivation-symptoms associated with dopaminergic hypofunction. We recently showed, in an open-label pilot study, that add-on pramipexole is a feasible treatment for depression with significant anhedonia, and that pramipexole increases reward-related activity in the ventral striatum. We will now confirm or refute these preliminary results in a randomised controlled trial (RCT) and an open-label follow-up study. METHODS AND ANALYSIS: Eighty patients with major depression (bipolar or unipolar) or dysthymia and significant anhedonia according to the Snaith Hamilton Pleasure Scale (SHAPS) are randomised to either add-on pramipexole or placebo for 9 weeks. Change in anhedonia symptoms per the SHAPS is the primary outcome, and secondary outcomes include change in core depressive symptoms, apathy, sleep problems, life quality, anxiety and side effects. Accelerometers are used to assess treatment-associated changes in physical activity and sleep patterns. Blood and brain biomarkers are investigated as treatment predictors and to establish target engagement. After the RCT phase, patients continue with open-label treatment in a 6-month follow-up study aiming to assess long-term efficacy and tolerability of pramipexole. ETHICS AND DISSEMINATION: The study has been approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. The study is externally monitored according to Good Clinical Practice guidelines. Results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05355337 and NCT05825235.