Background
Parkinson’s disease (PD) is a common, progressive, neurodegenerative condition that causes both motor (stiffness, slowness, rest tremor, and poor postural reflexes) and non-motor symptoms (abnormalities in mood, cognition, sleep, and autonomic function). The incidence of PD ranges from 8 to 18 per 100,000 person-years [
1], and thus identifying effective drugs that can slow the progression of PD is critical. PD is not purely a disorder of the basal ganglia; it also has systemic causes. For instance, a variety of mechanisms including oxidative stress, excitotoxicity, apoptosis, and mitochondrial dysfunction can all contribute to PD [
2,
3]. Additionally, disease pathogenesis results not only from the loss of dopaminergic neurons in the substantia nigra pars compacta but also from deposits of α-synuclein in the peripheral nervous system and deterioration of small nerve fibers [
4]. Existing drugs such as levodopa, dopamine agonists, monoamine oxidase inhibitors (MAO-B inhibitors), and catechol-O-methyltransferase inhibitors (COMT inhibitors) are not completely effective in PD patients. Therefore, neuroprotective agents such as creatine have increasingly been considered for their potential efficacy [
5‐
9].
Creatine is a natural compound that plays an important role in cellular energy homeostasis. It can be converted to phosphocreatine [
10], an energy intermediate that can then transfer a phosphoryl group to synthesize mitochondrial ATP. Creatine exhibits anti-apoptotic, anti-excitotoxic and direct antioxidative properties [
5]. Previous studies have reported that homocysteine accumulation may eventually lead to peripheral nerve damage [
11,
12] and that creatine exhibits neuroprotective and antioxidant properties [
13] by reducing homocysteine levels [
14]. Therefore, creatine may be effective in treating neurodegenerative diseases [
15‐
17].
Previous studies have reported conflicting results regarding the effect of creatine as a treatment for PD, and it remains unclear whether creatine treatment can improve clinical outcomes when compared with a placebo [
18‐
22]. Therefore, this meta-analysis was conducted to investigate the symptomatic efficacy of creatine versus placebo, analyzing outcomes assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Schwab & England Activities of Daily Living Scale.
Discussion
In our meta-analysis of five previously published papers, we assessed the effectiveness of creatine treatment versus placebo in PD patients. We found no association between creatine treatment and a decreased Total, Mental, ADL, or Motor UPDRS score, but we did note a greater improvement in Schwab & England Scale scores with use of creatine compared to placebo; however, this last test was included in 2 studies only. Both the UPDRS ADL and the Schwab & England Scale assess whether patients show improvement in ADL; however, this analysis indicated conflicting outcomes. Therefore, we believe that not enough evidence exists to support the theory that creatine can enhance ADL.
Conventional medications have been ineffective in curing PD to date, and creatine treatment has emerged as a potential method for slowing the progression of PD. Correlated basic studies have suggested that creatine does have a positive effect on PD patients, and these initial results led to the initiation of multiple clinical trials [
18‐
22]. However, consensus has not been reached on whether this treatment is effective, which is what prompted this meta-analysis. Our findings may provide clinicians with an alternative approach to treating PD. Although another meta-analysis on this subject was performed by Xiao et al. (2014) [
28] and involved two RCTs with a total of 194 patients, the findings were unreliable because of the high risk of bias, the small sample sizes and the short duration of the eligible trials. The efficacy of creatine treatment for PD requires data from clinical trials before any conclusions can be reached. The systematic review conducted here assessed the efficacy and safety of creatine as a primary or adjuvant treatment for PD. We included five RCTs [
18‐
22] that had a total of 1339 patients and compared creatine treatment with the administration of a placebo. To evaluate the PD patients’ prognosis, we assessed whether their UPDRS scores or Schwab & England Scale scores had changed after treatment. We addressed the limitations of the previous meta-analysis by performing a comprehensive and extensive literature search that evaluated RCTs using appropriate criteria, including a qualitative analysis of RCTs and the use of the GRADE approach to determine the quality of evidence. The quality of the studies was considered only moderate or low based on the following parameters: [
1] the included trials were reported as randomized, double-blind trials but did not provide additional details; [
2] moderate variation in baseline variables was observed among the studies; [
3] some comparisons exhibited heterogeneity; and [
4] creatine was used in combination with CoQ10 or minocycline [
18,
22]. The RCTs were generally of high quality, although we did include RCTs that involved diverse risks. Overall, the methodological quality of the 5 enrolled studies was considered good with respect to the most common and relevant biases.
Because the high number of patients enrolled in the study by Kieburtz et al. [
19] accounted for a large proportion of our overall analytical sample (955/1339; 71.3%), a sensitivity analysis was performed and found no evidence of significant heterogeneity. We found that this single study did influence the overall outcome, resulting in a significant decline in UPDRS Mental scores. Although a sensitivity analysis was performed and found no evidence of significant heterogeneity. This influence might be due to the large sample size, the longer follow-up duration or the high rate of drop-outs that had to be excluded. These and other confounding factors, such as follow-up duration, disease duration, and the baseline disease severity of the patients in each study, are fully described in Table
2. The baseline characteristics of the patient population were similar when initially assessed. Regarding follow-up duration, only the study by Kieburtz et al. [
19] lasted longer than 24 months. This parameter, together with the high rate of drop-outs in that same study, may account for the heterogeneity observed when examining the UPDRS Mental scores. Additionally, the disease duration in the study by Li et al. [
18] was longer than the duration reported in the other 4 studies, and this discrepancy may or may not have contributed to the significant heterogeneity observed.
There are some limitations to this meta-analysis. First, although we included three more studies than Xiao et al. (2014), the per-study and overall sample size remained small. Second, the disease outcomes were primarily assessed by the UPDRS and Schwab & England Scale, which may not cover other potential treatment benefits for patients with psychiatric and cognitive disorders. Finally, these studies lacked long-term assessments of key indicators, such as 5- or 10-year patient survival rates. Some of the trials were quite heterogeneous, with several reasonable explanations for this finding: [
1] the trials used different doses of creatine; [
2] two of the trials [
18,
22] used CoQ10 or minocycline as a co-intervention; [
3] all of the trials were reported as RCTs but did not provide additional details; [
4] the intervention was not confined to a single variant, which may have had indirect effects; and [
5] one study [
19] reported a high drop-out rate (greater than 20%.)
Based on this meta-analysis, we believe that creatine treatment is ineffective and that it has limited prospects as a drug of choice for PD. The limited efficacy of creatine in treating PD can be explained by several factors. First, the cellular transport of this substance is constrained [
29]. In a previous study, after patients were treated with creatine (3.4 g/d) for 4 weeks, brain creatine levels were only slightly elevated [
30]. Another factor is the insufficient dose administered. Compared to rodents, which were given 4 g of creatine per day in their food (133 g/kg), humans who received the highest dose of 10 g of creatine per day (0.15 g/kg for a 65-kg adult) still did not experience the same positive effects [
21]. Moreover, in a study that involved mitochondrial dysfunction, creatine was found to be significantly correlated with depression [
31]. One study we included in this analysis found that patients treated with creatine had a significantly better score on the Mental UPDRS (
P = 0.046) [
21], while another found that creatine combined with Coenzyme Q10 could delay the decline in cognitive function of patients with PD, as assessed by the Montreal Cognitive Assessment (MoCA) [
18]. Thus, in addition to focusing on the efficacy of creatine in relieving the motor symptoms of PD, we should also examine its effect on the psychiatric and cognitive symptoms.
Although the effectiveness of creatine in improving mitochondrial function has previously been demonstrated, it showed no effect on PD patients in this analysis. Accordingly, we hypothesize that mitochondrial dysfunction may play an indirect role in the development of PD, which may be susceptible to many other underlying but yet unknown factors. Therefore, the use of other neuroprotective agents to treat PD should still be investigated.
Acknowledgments
We would like to thank ZL for the excellent technical support.