Table 1.
List of articles on NMDA antagonists and Parkinson’s disease in PubMed Database (1969–2018)
| Study (year) | Drug, dose, duration | Population characteristics | Design | Measures | Findings | Limitations | Bias score |
|---|---|---|---|---|---|---|---|
| Aarsland et al. (2009) | Memantine 20 mg/day 24 weeks |
PD or LBD N = 72 |
Randomized, double-blinded placebo-controlled | CGI, MMSE, NPI, UPDRS | CGI score improved in patients given memantine (p = 0.03). Improved speed and global cognition led to the changes in CGI score. MMSE improvement (p = 0.02) although no significant differences in UPDRS and NPI scores. | High patient attrition and lacked adequate statistical power-grouped PD and DLB cohort | 2 |
| Wesnes et al. (2014) | Memantine 20 mg/day 24 weeks |
Disrupted episodic memory/cognition N = 30 PDD |
Randomized, double-blind, placebo-controlled multi-center |
CDR | Memantine produced statistically significant medium to large effect-sized improvements in attentional performance involving information processing and to verbal episodic recognition memory as evidenced by increased performance in choice reaction time, immediate, and delayed word recognition. | 2 | |
| Emre et al. (2010) | Memantine 20 mg/day 24 weeks |
PD N = 120 | Multi-center, randomized, double-blind, placebo-controlled | ADAS, NPI | NPI did not improve in PD (−1.6 vs. −0.1, respectively, difference of −1.4, p = 0.522) nor with ADAS (p = 0.576). | Small sample size, missing data at some time points | 2 |
| Leroi et al. (2009) | Memantine 20 mg/day, 16 weeks Washout and follow-up after 6 weeks (22-week) |
PDD N = 25 |
Randomized, double-blind, placebo-controlled | NPI, DRS, MMSE | NPI and MMSE changes between memantine and placebo were insignificant (sub-scores not shown). DRS changes between placebo (100.3) in favor of memantine (94.7). After washout, memantine group more often had global deterioration (70%) vs. (29%) for placebo. |
NPI sub-scores not shown, small sample size, some participants on cholinesterase inhibitors before trial | 2 |
| Litvinenko et al. (2008) | Memantine 20 mg/day 12, 24 week assessment |
PD N = 62 |
Placebo-controlled | ADAS-cog, Verbal Fluency Test, clock-drawing test NPI, FAB, DAD | At 24 weeks, memantine group had significant improvements in ADAS-cog (0.002), FAB (p = 0.01), verbal fluency test (p = 0.01), and clock drawing test (p = 0.03). NPI improvement with memantine, i.e., disinhibition (p = 0.006), irritability (p = 0.004), anxiety (p = 0.04), and hallucinations (p = 0.048). No significant changes at 12 weeks. At 52 weeks, significant improvements in all scales. |
Non-randomized, non-blinded | 2 |
| Johansson et al. (2010) | Memantine 20 mg/day 24 weeks 4 week washout additional 26 week trial |
PD and LBD n = 56 |
Washout and open label continuation after a double-blind randomized controlled trial | CGIC, presence of recurrence of symptoms upon drug withdrawal | Washout of memantine caused 9% (attrition due to worsening of psychiatric symptoms, i.e., anxiety and depression). CGIC scores worsened more in the memantine washout group vs. placebo. |
Grouped PD and DLB cohort | 2 |
| Vidal et al. (2013) | Memantine 20 mg/day ~ 3 months |
PD N = 2 |
Case report | Global UPDRS (I–III) | Global UPDRS showed improvement following treatment with memantine with the unanticipated improvement in LID and on–off phenomenon. For patient #2 = 4 point improvement in mood/behavior, no change in patient #1. | Small sample size | 2 |
| Leroi et al. (2014) | Memantine 20 mg/day 22 weeks |
PDD N = 25 |
Randomized, double-blind, placebo-controlled | GAS, PDQ-8, Zarit Burden Inventory |
A significantly greater proportion of participants on memantine (64%) had better than expected GAS outcomes compared with those on placebo (7%) (p = 0.007). GAS score, as well as mean caregiver burden score, from baseline to drug discontinuation was significantly greater in memantine compared to placebo (p = 0.03 and 0.04, respectively). Although significant differences in QOL were not seen, memantine improved individually set goals and caregiver burden in PDD. | Ungeneralizable outcome measures, small sample size, no measure of inter-rater reliability for GAS | 2 |
| Larsson et al. (2011) | Memantine 20 mg/day 24 weeks |
PDD or LBD N = 70 |
Randomized, double-blind, placebo-controlled | Caregiver-rated QOL-Alzheimer’s Disease in domains (WHO health classification) | Memantine significantly improved total QOL in both PDD and LBD patients (p = 0.01), memantine had 42% rate higher QOL than at baseline compared to 15% in placebo. | Small sample size, some patient attrition, possible response shift phenomenon | 2 |
| Ondo et al. (2011) | Memantine 20 mg/day 8 weeks |
PD N = 40 |
Double-blind placebo-controlled exploratory pilot trial | UPDRS I–II ESS, HAM-D, QOL-39, CGI |
No significant change in UPDRS section I or II, Epworth sleepiness scale, fatigue severity scale, Hamilton depression scale, Conner adult inventory, PD Quality of Life-39, or clinical global impressions. | Short time period, only 8-week follow-up | 1 |
| Larsson et al. (2010) | Memantine 20 mg/day 24 weeks |
PDD and LBD Excessive daytime sleepiness and REM disorder in PDD N = 20 (PDD + DLB) |
Randomized, double-blind, placebo-controlled | Stavanger sleep questionnaire and ESS | At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness. | Small sample size, some patient attrition, possible awareness bias due to methodology | 2 |
| Pahwa et al. (2015) | Amantadine ADS‐5102 extended-release (260–420 mg/day) 8 weeks |
PD patients with levodopa-induced dyskinesia N = 83 |
Randomized, double-blind, placebo-controlled, multisite study | UPDRS (I–III), PDQ-39 |
Insignificant change in UPDRS and QOL/PDQ-9 at week 8 for any dose. | UPDRS I score combined with II–III so effect on mood cannot be determined Focus was on safety of novel formulation (extended release) |
1 |
| Bandini et al. (2002) | Amantadine 100 mg/day/1st week 200 mg/day/2nd week 300 mg/day/3rd week 6 months |
PD N = 23 Cognition and visual response |
Open-label cohort study with amantadine monotherapy vs. adjuvant levodopa | Event related P300 (visual discrimination paradigm) | Amantadine alone and as adjuvant to levodopa can significantly improve both the speed of visuo-cognitive processing and shortened latency of visual discrimination (p < 0.05). | Small sample size, non-randomized, single ethnicity (African-American) | 2 |
| Parkes et al. (1970) | Amantadine 100 mg/day (2 weeks) 300 mg/day (2 weeks) 500 mg/day (2 weeks) 6 week trial |
PD N = 43 |
Cohort study | Self-designed motor, sensory and psychological tests, patient report | During trial, 26/43 patients reported improved “mood”, regardless of dose. | Non-randomized, non-placebo-controlled, small sample size, unverified techniques to measure PD symptoms | 0 |
| Schwab et al. (1969) | Amantadine 100–200 mg/day 6 months |
PD N = 163 |
Cohort study without a placebo control | Patient report | 20% of patients experienced side effects of increased jitteriness, insomnia, abdominal uneasiness, loss of appetite, and slight subjective dizziness. One patient reported a feeling of depression. 22% of patients experienced insomnia, dizziness, confusion. One patient reported depression after amantadine. | Non-randomized, non-placebo-controlled, no description of how symptoms were quantified following drug administration | 1 |
| Sherman et al. (2016) | Ketamine 0.15–0.3 mg/kg/h 50–96 h periods |
PD N = 5 Pain and depression |
Case reports | Patient report | Depression and suicidality improved in one depression-positive patient (measure is not stated). However, the patient continued to exhibit mild symptoms of depression in follow-up visits. Pain improved for all five patients: two back pain, two headache and one painful dyskinesia. | Small sample size, multiple unspecified metrics used to measure outcomes | 1 |
| Schneider et al. (2000) | D-cycloserine 320, 1000, 8000 µg/kg Dizocilpine (10–32 µg/kg) (single) |
MPTP-induced PD primate model N = 4 |
Animals served as their own controls with and without treatment | Performance of a variable-delayed-response task | D-cycloserine significantly improved performance of a variable-delayed-response task. No effect at cycloserine 8000 µg/kg or with dizocilpine. | Small sample size, animal model | a |
| Ho et al. (2011) | D-cycloserine 30 mg/kg/day 100 mg/kg/day 200 mg/kg/day (13 days) |
MPTP-induced PD rat model | Animals served as their own controls | Rotarod test, T-maze, plus-maze | Treatment with D-cycloserine improved deficits in working memory and anxiety-like behavior. | Small sample size, animal model | a |
| Singh et al. (2017) | Dizocilpine 0.2 mg/kg, ip |
6-OHDA-induced PD rat model anxiety and depression |
Experimental | Light chamber (time spent) social interaction test (anxiety-like behavior) immobility test (depression) |
Dizocilpine-treated rats spent more time in the light chamber (p < 0.01), and more contact time during the social interaction test (p < 0.05) in comparison to 6-OHDA lesioned rats. | Animal model | a |
| Montastruc et al. (1994) | Dextromethorphan 90–180 mg/day 1 month |
PD n = 10 global symptoms |
Open label | UPDRS (I–III) | No significant improvement in UPDRS subscores of extrapyramidal symptoms (partial tremor, rigidity, bradykinesia) mentation, behavior, and mood or daily activity. | Small sample size, specific changes in UPDRS score not provided | a |
| Quality assessment criteria for selected studies | ||
|---|---|---|
| Score | Method for measuring non-motor symptoms | Trial period |
| 1 | Subjective, self-reports by patient or qualitative noting by clinician | Adequate time period |
| 0 | Objective measure, either by clinician (UPDRS-1, MMSE, ADAS, etc.) or by caregiver (NPI) | Inadequate time period, less time than average trials for given drug |
Abbreviations: ADAS-Cog Alzheimer’s disease assessment scale-cognitive, CDR clinical dementia rating, CGI clinical global impressions, DAD disability assessment for dementia, ESS Epworth sleepiness scale, FAB frontal assessment battery, GAS goal attainment scaling, HAM-D Hamilton depression rating scale, MMSE mini-mental state examination, PDQ-8/39 Parkinson’s disease questionnaire-8/39-item, NPI neuropsychiatric inventory, and UPDRS unified Parkinson’s disease rating scale
a Bias assessment was not completed with animal studies