Dymowski et al.

(2017)

Australia

RCT

PEDro=9

N_Initial=11, N_Final=10

Population: TBI. Methylphenidate Group (n=6): Mean Age=35 yr; Gender: Male=4, Female=2; Mean Time Post Injury=366 d; Mean Worst GCS=4.83. Placebo Group (n=4): Mean Age=32.5 yr; Gender: Male=2, Female=2; Mean Time Post Injury=183.5 d; Mean Worst GCS=4.50.

Intervention: Participants were randomly assigned to receive either methylphenidate (0.6 mg/kg/d rounded to the nearest 5mg with maximum daily dose of 60 mg) or placebo (lactose). Outcomes relating to processing speed, complex attentional functioning, and everyday attentional behaviour were assessed at baseline, 7 wk (on-drug), 8 wk (off-drug), and 9mo follow-up.

Outcome Measures: Symbol Digit Modalities Test (SDMT), Trail Making Test (TMT) A and B; Hayling (A, B, error),  Digit Span (DS-Forward, Backward, Sequencing, Total), Ruff 2&7 Selective Attention Test Automatic Speed Raw Score (2&7 ASRS), Ruff 2&7 Selective Attention Test Controlled Speed Raw Score (2&7 CSRS), Simple Selective Attention Task Reaction Time (SSAT RT), Complex Selective Attention Task Reaction Time (CSAT RT), N-back 0-back RT, N-back 1-back RT, N-back 2-back RT, Rating Scale of Attentional Behaviour Significant Other (RSAB SO).

Zhang and Wang

(2017)

China

RCT

PEDro=10

N_Initial=36, N_Final=33

Population: TBI; Severity: mild to moderate. Methylphenidate Group (n=18): Mean Age=36.3 yr; Gender: Male=13, Female=5. Placebo Group (n=18): Mean Age=34.9 yr; Gender: Male=14, Female=4.

Intervention: Participants were randomly assigned to receive methylphenidate (flexibly titrated from 5 mg/d at the beginning, then gradually increased by 2.5 mg/d until reaching 20 mg/d) or placebo for 30 wk.

Outcome Measures: Mental Fatigue Scale (MFS), Choice Reaction Time (CRT), Compensatory Tracking Task (CTT), Mental Arithmetic Test (MAT), Digit Symbol Substitution Test (DSST), Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAMD).

1.        At baseline, there were no significant differences between groups in terms of demographics, MFS, CRT, CTT, MAT, DSST, MMSE, BDI, or HAMD.

2.        Post-intervention, the experimental group had significantly lower scores compared to control group for MFS (p=0.005), CRT (p<0.001), CTT (p<0.001), BDI (p=0.040), and HAMD (p=0.005).

3.        Post-intervention, the experimental group had significantly higher scores compared to control group for MAT (p=0.020), DSST (p<0.001), MMSE (p<0.001).

Willmott et al.

(2013)

Australia

RCT

PEDro=10

N=32

Population: TBI; Gender: Male=21, Female=11; Mean Time Post Injury=68 d; TBI Val/Val Group (n=11): Mean Age=22.64 yr; Mean GCS=4.67; TBI Val/Met Group (n=14): Mean Age=28.57 yr; Mean GCS=5.38; TBI Met/Met Group (n=7): Mean Age=30.57 yr; Mean GCS=6.83.

Intervention: Participants with TBI, in a crossover design, received 0.3 mg/kg methylphenidate (2 ×/d) for 6 sessions in total (spanning 2 wk), alternating between treatment and placebo for every other session. Results were compared against those from healthy controls (n=40). Groups were stratified by the presence of the Val158Met gene.

Outcome Measures: Ruff 2 & 7 Selective Attention Test – automatic (2 & 7 ASRS) and controlled (2 & 7 CSRS), Selective Attention Task, Four Choice Reaction Time Task (4CRT) – dissimilar compatible (DC) and similar incompatible (SI), Symbol Digit Modalities Test (SDMT), Letter Number Sequencing Task,  Wechsler Test of Adult Reading.

1.        At baseline, there were no significant differences across various genotypes on attentional performance.

2.        Participants with TBI and Met/Met alleles performed significantly poorer on the SDMT (p<0.0005), 2 & 7 ASRS (p=0.001), 2 & 7 CSRS (p<0.0005), DC RT (p=0.005), and SI RT (p=0.002), when compared to controls. Analyses with participants with TBI and Val/Val alleles showed even worse outcomes, demonstrating poorer performance on 7/8 outcome measures.

3.        Following methylphenidate treatment one significant drug and genotype interaction was seen between Met/Met carriers and performance on the SDMT (F=4.257; p=0.024), suggesting Met/Met carriers were more responsive to methylphenidate than either of the others.

Kim et al.

(2012)

USA

RCT

PEDro=7

N=23

Population: Moderate/Severe TBI; Mean Age=34.2 yr; Gender: Male=18, Female=5; Mean Time Post Injury=51.1 mo.

Intervention: In a crossover design, participants were randomly assigned to receive 0.3 mg/kg methylphenidate followed by placebo, or the reverse and were assessed after each.

Outcome Measures: Visual sustained attention task (VSAT), Two-back task.

1.        Relative to placebo, both accuracy (1.62±1.03 versus 2.23±1.07; p<0.005) and mean reaction time (827.47±291.17s versus 752.03±356.87s; p<0.050) in the VSAT were improved significantly on MPH.

2.        Relative to placebo, mean reaction time (929.31±192.92s versus 835.02±136.12s; p<0.050), but not accuracy, in the two-back task was improved significantly when on MPH.

Willmott & Ponsford

(2009)

RCT

PEDro=10

N=40

Population: TBI; Mean Age=26.93 yr; Gender: Male=28, Female=12; Time since injury=68.38 d.

Intervention: Patients received either methylphenidate (0.3 mg/kg 2 x/d, rounded to the nearest 2.5 mg) or a placebo. Patients were seen for 6 sessions across 2-week period. Patients then crossed-over.

Outcome Measures: Ruff 2 and 7 Selective Attention Test, Selective Attention Task, Four Choice Reaction Time Task, Sustained Attention to Response Task, Symbol Digit Modalities Test, Letter Number Sequencing Task, Wechsler Test of Adult Reading.

Kim et al.

(2006)

Korea

RCT

PEDro=6

N=18

Population: TBI; Methylphenidate Group (n=9): Mean Age=30.1 yr; Gender: Male=9, Female=0; Mean Time Post Injury=1.6 yr; Placebo Group (n=9): Mean Age=38.3 yr; Gender: Male=7, Female=2; Mean Time Post Injury=3.6 yr.

Intervention: Patients were randomly allocated to receive either 20 mg methylphenidate or the placebo. Assessments were done at baseline (T1), 2 hr post treatment (T2), and 2 d later (T3).

Outcome Measures: Visual sustained attention task (VSAT), Two-back task.

1.        At T1 there were no significant differences in mean reaction time or in accuracy between the two groups.

2.        For those in the treatment group, the mean reaction time of the two-back task improved significantly compared to those in the placebo group from T1 to T2 (13.74±13.22% versus 4.02±9.48%; p<0.05).

3.        No significant difference in improvement as seen with accuracy of the two-back task (p=0.07), nor with the VSAT.

Whyte et al.

(2004)

USA

RCT

PEDro=8

N=34

Population: TBI; Mean Age=37 yr; Gender: Male=29, Female=5; GCS<12; Median Time Post Injury=3.2 yr.

Intervention: Participants received 0.3 mg/kg/dose methylphenidate for 3 wk, 2×/d, and placebo for 3 wk, for a total of 6 wk, with conditions alternating weekly. Washout lasted a day, after which time the groups crossed over.

Outcome Measures: Attention Tasks.

1.        Methylphenidate showed significant improvements in information processing speed (p<0.001), work task attentiveness (p=0.010), and caregiver attention ratings (p=0.010), pre-post.

2.        No treatment-related improvements were observed in susceptibility to distraction and divided or sustained attention.

Plenger et al.

(1996)

USA

RCT

PEDro=5

N=23

Population: TBI; Gender: Male=17, Female=6; Placebo Group (n=13): Mean Age=26.6 yr; Mean GCS=8.1; Methylphenidate Group (n=10): Mean Age=31.4 yr; Mean GCS=9.3.

Intervention: Patients were randomly allocated to receive either methylphenidate or placebo. Methylphenidate was administered at 30 mg/kg, 2×/d, for 30 d.

Outcome Measures: Disability Rating Scale (DRS), Continuous Performance Test (CPT), 2 & 7 Test (2 & 7), Paced Auditory Serial Addition Test (PASAT), Digit Span & Attention/ Concentration from Wechsler Memory Scale-Revised (Attn/Conc from WMS-R).

1.        At 30 d follow-up (n=15), significant differences were obtained on DRS, suggesting better outcome for the methylphenidate group. This difference however was not seen at 90 d follow-up (n=11).

2.        Significant differences were found on the attention-concentration domain at the 30 d follow-up, as indicated by CPT, PASAT, 2 & 7, and Attn/Conc from WMS-R (p<0.030). The treatment group performed better in these measures compared to the placebo group.

Speech et al.

(1993)

USA

RCT

PEDro=7

N=12

Population: TBI; Mean Age=27.6 yr; Gender: Male=5, Female=7; Mean Time Post Injury=48.5 mo.

Intervention: In a crossover design, participants were randomly assigned to receive 0.3 mg/kg methylphenidate, 2 ×/d, for 1 wk, followed by 1 wk of placebo, or receive the treatment in the reverse order.

Outcome Measures: Gordon Diagnostic System, Digit Symbol and Digit Span subtests of the Wechsler Adult Intelligence Scale-Revised, Stroop Interference Task, Sternberg High Speed Scanning Task, Selective Reminding Test, Serial Digit Test, Katz Adjustment Scale.

Gualtieri & Evans

(1988)

United States

RCT Crossover

PEDro=7

N=15

Population: Mean age=24.1yr; Gender: Male=10, Female=5; Mean time post-injury=46.8mo.

Intervention: Participants were assigned to receive three conditions in randomized order. 1) Placebo; 2) Methylphenidate (0.15mg/kg) twice daily; 3) Methylphenidate (0.30mg/kg) twice daily. Each condition was 12 days long, with 2 days washout between conditions.

Outcomes: Adult Activity Scale self-administered (AAS-S), Adult Activity Scale (administrator)(AAS-O), Examiner’s Rating Scale (EXRS), Self Rating Scale (SRS), Verbal Fluency Test (VFT), Non-verbal Fluency test (NVFT).

1.        There was a significant improvement in AAS-S and AAS-O scores between the placebo and high-dose conditions (p<0.05).

2.        There was a significant difference in SRS scores between the placebo group and the high-dose condition (p<0.05).

3.        On the EXRS there was a significant difference between baseline and low-dose (p=0.012), placebo and low-dose (p=0.025), baseline and high-dose (p=0.012), with higher doses of methylphenidate having improved effects.

4.        There was a significant improvement in VFT scores between baseline and the high-dose groups (p=0.017).

5.        There was a significant difference on NVFT scores between baseline and placebo (p=0.008), baseline and low-dose (p=0.008), baseline and high-dose (p=0.008), and the placebo and high-dose group (p=0.018), with methylphenidate improving scores.

Whyte et al.

(1997)

United States

RCT Crossover

PEDro=7

N=19

Population: Mean age=30.7yr; Gender: Male=15, Female=4; Mean GCS=5.83.

Intervention: Individuals were randomly assigned to either receive methylphenidate first or placebo, and then the reverse. Methylphenidate was given twice a day at a dose of 0.25mg/kg.

Outcomes: Sustained arousal task, phasic arousal task, distraction task, choice reaction-time task, behavioral inattention.

1.        There was a significant drug x performance interaction (p<0.001), where performance was differentially impacted by the drug on each assessment.

2.        Group stratification revealed that methylphenidate was more effective for improving performance on attentional measures for younger participant than older ones (p<0.05).

3.        There were no other significant effects.

Pavlovskaysa et al.

(2007)

Pre-Post

Israel

N=6

Population: TBI; Age Range=18-47 yr; Gender: Male=4, Female=2; GCS ≥8.

Intervention: Participants were administered 5 to 10 mg of methylphenidate (MHP) over a 2-week period. Participants were evaluated before, during and after the administration of methylphenidate.

Outcome Measure: Performance on the Visual Spatial Attention Task Analyzing Rightward and Leftward Shifts of Attention.

1.        Prior to treatment, patients were found to have great difficulty in shifting attention between hemifields.

2.        There was a significant improvement in the asymmetry with MHP (p<0.001).

3.        The right-side performance was significantly better on average than the left side (0.77 versus 0.59; p<0.050).

4.        Performance was significantly better for ipsilateral valid cueing (p<0.010) than for invalid cross-trials (p<0.001).

5.        The difference between ipsi- and cross-cueing for left side target performance is significant for each of the stages (p<0.001).