Table 2.

RCT using pharmacological interventions.

Authors (and year)	Population	Time since injury	Intervention (type, dosage, duration, frequency)	Primary outcome measures	Outcome findings
Tenovuo (2004)	111 adults with TBI	71 ± 6.7 months	Central acetylcholinesterase inhibitor (CAI): 27 patients took donepezil once a day (7.2 mg mean), 30 took galantamine twice a day (5 mg mean), and 54 took rivastigmine twice a day (2.3 mg mean). Average duration of the treatment was 18.4 months (6–33 months).	Patient-Reported Outcomes, Glasgow Outcome Scale—Extended	No improvement in self-reported outcomes and Glasgow outcome scale was detected across all 3 treatment types.
	Mild—58%
	Moderate—10%
	Severe—32%
Zhang (2004)	18 adults with TBI (the severity ranged from GCS 3–15)	Cross-over design	Donepezil: A-B vs. B-A design with Donepezil (A) or placebo (B) for 10 weeks each with a 4-week washout period. Dosage was 5 mg/d for the first 2 weeks then 10 mg/d for the last 8 weeks	Auditory Immediate Index (AII), Visual Immediate Index (VII), Wechsler Memory Scale-III, and Paced Auditory Serial Addition Test (PASAR)	Intragroup comparison showed significant increases in AII, VII, and PASAT scores compared to baseline, whereas placebo condition did not change any of the outcomes.
		Group A: 4.6 ± 0.7 months
		Group B: 3.9 ± 0.5 months
Kim (2006)	18 adults with TBI (no description of the initial TBI severity)	Treatment: 1.6 ± 0.5 years	Methylphenidate: 20 mg or placebo was given 2 days after baseline then participants were tested 2 h and 2 days post treatment.	Working memory task and endogenous visuospatial attention tasks	The treatment group showed a significant improvement in working memory tasks and visuospatial attention when compared to placebo at 2 h post, but no group difference was found after 2 days.
		Control: 3.6 ± 3.4 years
Silver (2006)	157 adults with mild to severe TBI	Con: 103.4 ± 85.1 months	Rivastigmine: Participants would take 3 to 6 mg/day twice a day or a placebo for 12-weeks	Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing (CANTAB-RVIP) A’ subtest and the Hopkins Verbal Learning Test (HVLT)	There were no significant differences in CANTAB-RVIP and HVLT scores between treatment and placebo groups.
		Experimental: 79.9 ± 78.7 months
Amitabh (2008)	51 adults with TBI	Group A: 5.61 ± 4.76 years	Modafinil: Subjects were in a 10-week treatment or placebo phase followed by a 4 week washout period and then switched groups for 10 weeks. The treatment consisted of taking 100 mg/day for 3 days, then 100 mg twice a day for 11 days, followed by 200 mg twice a day for 8 weeks.	Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS)	No significant differences were found between modafinil and placebo in FSS at week 4 or week 10. Modafnil improved ESS score (less sleepy) at week 4 compared to placebo, but no group difference in ESS at week 10.
	Initial severity:
	Mild: 25.5%
	Moderate: 23.5%
	Severe: 51%	Group B: 5.95 ± 5.29 years
High (2010)	23 adults with moderate/severe TBI	Con: 5.1 ± 3.6 years	RhGH: Participants took a starting dose of 200 μg/d and increased 200 μg every month up to 600 μg for a year or took a placebo.	Neuropsychological measures: language, visual/spatial functioning, upper extremity motor functioning, information processing efficiency, working memory/attention, learning and memory, executive functioning, intellectual functioning, and emotional functioning	Improvements were found in the treatment group compared to placebo in dominant hand finger tapping test, Wechsler Adult Intelligence Scale III-Information Processing Speed Index, California Verbal Learning Test II, and the Wisconsin Card Sorting Test (executive function)
		Experimental: 11.0 ± 9.2 years
Kaiser (2010)	20 adults with mild to severe TBI	Treatment: 1.8 ± 0.9 years	Modafinil: Experimental group took 100 mg/day or twice a day if dose was effective and without side effects for 6 weeks, or placebo	Excessive daytime sleepiness (EDS), Epworth Sleepiness Scale, Fatigue Severity Scale	EDS improved significantly when taking Modafinil. There was no difference in posttraumatic fatigue between groups.
		Control: 2.0 ± 1.2 years
Giacino (2012)	184 adults with severe TBI	Experimental: 36–66 days	Amantadine: 100 mg doses were provided twice a day for 2 weeks, doses then increased to 150 mg for week 3, and 200 mg for week 4 if DRS scores did not improve by 2 points in the experimental group. The control group did not receive Amantadine treatment.	Disability Rating Scale (DRS)	Recovery was significantly faster in the treatment group during the 4-week treatment period. However, after the 2-week washout period, the DRS scores became similar between groups.
		Con: 37–65 days
Johansson (2013)	24 adults with mild/moderate TBI	Patients: 8.6 ± 0.5.1 years	Methylphenidate: Participants underwent three 4-week trials in one of three sequences: (1) no medication, low dose, normal dose, (2) low dose, normal dose, no medication, or (3) normal dose, no medication, low dose.	Mental Fatigue Scale (MFS)	Normal dose of Methylphenidate led to the greatest improvement in MFS score compared to low and no dose. Low dose also showed modest, but significant improvement in MFS compared to the no dose condition.
Theadom (2013)	60 adults with mTBI	Group A: 7.1 ± 2.66 months Group B: 8.04 ± 2.46 months	Enzogenol: 1000 mg of Enzogenol or placebo for 6 weeks, then Enzogenol for 6 additional weeks for all participants followed by placebo for 4 weeks	Cognitive Failures Questionnaire (CFQ), digit span subtest of the Wechsler Adult Intelligence Scale-III, Arithmetic and Letter Number Sequencing of the Wechsler Adult Intelligence Scale-IV	The treatment condition showed a significant reduction (improvement) in self-reported cognitive failures of the CFQ at week 6 compared to the placebo condition. No other outcomes showed significant result.
Menn (2014)	117 adults with severe TBI	1–10 years	Armodafinil: Participants received 50, 150, or 250 mg/day or a placebo dose for 12 weeks.	Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS), Clinical Global Impression-Change (CGI-C) TBI-Work Instability Scale (TBI-WIS), Clinical Global Impression-Severity Illness (CGI-S), and tolerability	Mean sleep latency was significantly improved in the group taking 250 mg/day compared to placebo. ESS and TBI-WIS scores did not show any significant differences between any group comparison.
Ripley (2014)	55 adults with moderate/severe TBI	Experimental: 8.2 ± 6.1 years	Atomoxetine: Experimental group took 40 mg twice a day for 2 weeks compared to a placebo pill for the control group.	Cognitive Drug Research (CDR) Computerized Cognitive Assessment System	There were no significant group differences in any of the cognitive metrics.
		Control: 6.6 ± 5.5 years
Hammond (2015)	168 adults with moderate/severe TBI	>6 months	Amantadine: 100 mg doses were given twice a day for 60 days for the treatment group, and an equivalent placebo was given to the control group.	Neuropsychiatric Inventory (NPI-I) Most Problematic Item—a scale for irritability assessment	There were no significant improvements seen in either group for NPI-I Most Problematic item.
Lequerica (2015)	13 adults with mild/moderate TBI	62.1 ± 91.5 months	Ramelteon: nightly dosage of 8 mg or a placebo for a 3-week period followed by a 2 week washout and underwent alternative intervention for 3 weeks.	Sleep/wake patterns, mood, daytime sleepiness, fatigue, and Neurocognitive Index	Total sleep time and executive functioning had a significant increase in the treatment group compared to placebo.
Berginstrom (2017)	64 adults with mild/moderate TBI	Treatment: 8.58 ± 6.84 years	Monoaminergic: Experimental group received 5 mg of -OSU6162 twice a day in week 1, 10 mg twice a day in week 2, 15 mg twice a day in week 3 and 4 compared to placebo group.	Fatigue Severity Scale, Mental Fatigue Scale	Both groups showed significant improvements in both outcomes at follow-up and reported no between group differences.
		Control: 8.10 ± 7.43 years
Hart (2017)	32 adults with moderate/severe TBI	Experimental: 53.6 ± 25.1 days	Dextroamphetamine (DEX): 10 mg or placebo daily for 3 weeks	Rate of functional recovery, attention, engagement in therapy, and mood	DEX did not lead to significant improvement in any functional and cognitive outcomes.
		Control: 60.2 ± 37.4 days
Dorer (2018)	14 adults with moderate/severe TBI	23.43 ± 12.25 months	Methylphenidate: Participants took 30 mg or a placebo 75 min prior to an MRI in counterbalanced order. Scans were on average 2 weeks apart.	Sequential finger opposition fMRI paradigm	Methylphenidate resulted in faster reaction times in patients but was not significant compared to controls. fMFI also found the left inferior frontal gyrus to be activated significantly more compared to when on the placebo.
Theadom (2018)	78 adults with mild/moderate TBI	Treatment: 98 days	NeuroAiD II: Participants took MLC901 0.8 g capsules 3 times a day for 6 months or took a placebo.	Cognitive function assessed by the CNS Vital Signs online neuropsychological test.	The treatment group showed significant improvements in executive functioning and complex attention at 6 months compared to the placebo group.
		Control: 94.5 days