Pharmacotherapy for chronic cognitive impairment in traumatic brain injury

Dominic Dougall; Norman Poole; Niruj Agrawal

doi:10.1002/14651858.CD009221.pub2

Liječenje lijekovima za kronični kognitivni poremećaj u traumatskoj ozljedi mozga

Contraer todo Desplegar todo

Referencias

References to studies included in this review

Ir a:

estudios excluidos
estudios en curso
otras referencias
otras versiones publicadas

Jha A, Weintraub A, Allshouse A, Morey C, Cusick C, Kittelson J, et al. A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. Journal of Head Trauma Rehabilitation 2008;23(1):52‐63.

Johansson B, Carlsson A, Carlsson MA, Karlsson M, Nilsson MKL, Nordquist‐Brandt E, et al. Placebo‐controlled cross‐over study of the monoaminergic stabiliser (‐)‐OSU6162 in mental fatigue following stroke or traumatic brain injury. Acta Neuropsychiatrica 2012;24(5):266‐74.

Ripley DL, Morey CE, Gerber D, Harrison‐Felix C, Brenner LA, Pretz CR, et al. Atomoxetine for attention deficits following traumatic brain injury: Results from a randomized controlled trial. Brain Injury 2014;28(12):1514‐22.

Silver JM, Koumaras B, Chen M, Mirski D, Potkin SG, Reyes P, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology 2006;67(5):748‐55.

References to studies excluded from this review

Ir a:

estudios incluidos
estudios en curso
otras referencias
otras versiones publicadas

Johansson B, Wentzel A‐P, Andréll P, Mannheimer C, Rönnbäck L. Methylphenidate reduces mental fatigue and improves processing speed in persons suffered a traumatic brain injury. Brain Injury 2015;29(6):758‐65.

León‐Carrión J, Dominguez‐Roldán JM, Murillo‐Cabezas F, del Rosario Dominguez‐Morales M, Muñoz‐Sanchez MA. The role of citicholine in neuropsychological training after traumatic brain injury. NeuroRehabilitation 2000;14(1):33‐40.

Plenger PM, Dixon CE, Castillo RM, Frankowski RF, Yablon SA, Levin HS. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double‐blind placebo‐controlled study. Archives of Physical Medicine and Rehabilitation 1996;77(6):536‐40.

Schneider WN, Drew‐Cates J, Wong TM, Dombovy ML. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double‐blind placebo‐controlled study. Brain Injury 1999;13(11):863‐72.

Speech TJ, Rao SM, Osmon DC, Sperry LT. A double‐blind controlled study of methylphenidate treatment in closed head injury. Brain Injury 1993;7(4):333‐8.

Tenovuo O, Alin J, Helenius H. A randomized controlled trial of rivastigmine for chronic sequels of traumatic brain injury—What it showed and taught?. Brain Injury 2009;22(6):548‐58.

References to ongoing studies

Ir a:

estudios incluidos
estudios excluidos
otras referencias
otras versiones publicadas

Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI (RIVET). Ongoing studySeptember 2012.

Additional references

Ir a:

estudios incluidos
estudios excluidos
estudios en curso
otras versiones publicadas

Adams JH, Graham DI, Gennarelli TA, Maxwell WL. Diffuse axonal injury due to non‐missile head injury. Journal of Neurology, Neurosurgery, and Psychiatry 1991;54(6):481‐3.

Aharon‐Peretz J, Tomer R. Traumatic brain injury. In: BL Miller, JL Cummings editor(s). The Human Frontal Lobes: Functions and Disorders. 2nd Edition. New York: The Guilford Press, 2007:540‐51.

Google Scholar

Arciniegas D, Adler L, Topkoff J, Cawthra E, Filley CM, Reite M. Attention and memory dysfunction after traumatic brain injury: cholinergic mechanisms, sensory gating, and a hypothesis for further investigation. Brain Injury 1999;13(1):1‐13.

Bernstein DM. Recovery from mild head injury. Brain Injury 1999;13(3):151‐72.

Brooks DN. Wechsler Memory Scale performance and its relationship to brain damage after severe closed head injury. Journal of Neurology, Neurosurgery and Psychiatry 1976;39(6):593‐601.

Brown SJ, Fann JR, Grant I. Postconcussional disorder: time to acknowledge a common source of neurobehavioural morbidity. The Journal of Neuropsychiatry and Clinical Neuroscience 1994;6(1):15‐22.

Google Scholar

Burstein ES, Carlsson ML, Owens M, Ma J‐N, Schiffer HH, Carlsson A, et al. In vitro evidence that (‐)‐OSU6162 and (+)‐OSU6162 produce their behavioural effects through 5‐HT2A serotonin and D2 dopamine receptors. Journal of Neural Transmission 2011;118(11):1523‐33.

Carlsson ML, Burstein ES, Kloberg A, Hansson S, Schedwin A, Nilsson M, et al. In vivo evidence for partial agonist effects of (‐)‐OSU6162 and (+)‐OSU6162 on 5‐HT2A serotonin receptors. Journal of Neural Transmission 2011;118(11):1511‐22.

Chalmers TC, Celano P, Sacks HS, Smith H. Bias in treatment assignment in controlled clinical trials. New England Journal of Medicine 1983;309(22):1358‐61.

Cooper JR, Bloom FE, Roth RH (editors). Dopamine. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press, 1991:285‐332.

Google Scholar

Cooper JR, Bloom FH, Roth RH (editors). Norepinephrine and epinephrine. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press, 1991:220‐84.

Google Scholar

Cooper JR, Bloom FE, Roth RH (editors). Serotonin and histamine. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press, 1991:338‐80.

Google Scholar

Department of Health. The National Service Framework for Long‐term Conditions. www.dh.gov.uk/PublicationsAndStatistics/Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ID=4105361&chk=jl7dri.

Fleminger S, Ponsford J. Long term outcome after traumatic brain injury. British Medical Journal 2005;331(7530):1419‐20.

Gentry LR, Godersky JC, Thompson B. MR imaging of head trauma: review of the distributions and radiopathologic features of traumatic lesions. American Journal of Roentgenology 1988;150(3):663‐72.

Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler NR. Inhibition of acetyl‐ and butyryl‐cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit. Journal of Neural Transmission 2002;109(7‐8):1053‐65.

Griffin SL, van Reekum R, Masanic C. A review of cholinergic agents in the treatment of neurobehavioral deficits following traumatic brain injury. The Journal of Neuropsychiatry and Clinical Neurosciences 2003;15(1):17‐26.

Hayes RL, Lyeth BG, Jenkins LW. Neurochemical mechanisms of mild and moderate head injury: implications for treatment. In: Levin HS, Eisenberg HM, Benton AL editor(s). Mild Head Injury. New York: Oxford University Press, 1989.

Google Scholar

Heilman KM, Watson RT, Valenstein E. Neglect and related disorders. In: KM Heilman, E Valenstein editor(s). Clinical Neuropsychology. New York: Oxford University Press, 1993:279‐336.

Higgins JPT, Green S (Editors). Cochrane Handbook for Systematic Reviews and Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Himanen L, Portin R, Isoniemi H, Helenius H, Kurki T, Tenovuo O. Longitudinal cognitive changes in traumatic brain injury: a 30‐year follow‐up study. Neurology 2006;66(2):187‐92.

Jennett B, Bond M. Assessment of outcome after severe brain damage: a practical scale. Lancet 1975;305(7905):480‐4.

Kay T, Harrington DE, Adams R, Anderson T, Berrol S, Cicerone K, et al. Definition of mild traumatic brain injury. Journal of Head Trauma Rehabilitation 1993;8(3):86‐7.

Koponen S, Taiminen T, Portin R, Himanen L, Isoniemi H, Heinonen H, et al. Axis I and II psychiatric disorders after traumatic brain injury: a 30‐year follow‐up study. American Journal of Psychiatry 2002;159(8):1315‐21.

Lathi R, Tamminga CA, Carlsson A. Stimulating and inhibitory effects of the dopamine "stabiliser" (‐)‐OSU6162 on dopamine D(2) receptor function in vitro. Journal of Neural Transmission 2007;114(9):1143‐46.

Lippert‐Gruner M, Kuchta J, Hellmich M, Klug N. Neurobehavioural deficits after severe traumatic brain injury (TBI). Brain Injury 2006;20(6):569‐74.

Lu J, Gary KW, Neimeier JP, Ward J, Lapane KL. Randomized controlled trials in adult traumatic brain injury. Brain Injury 2012;26(13‐14):1523‐48.

McDowell S, Whyte J, D'Espositon M. Working memory impairments in traumatic brain injury: evidence from a dual‐task paradigm. Neuropsychologia 1997;35(10):1341‐53.

Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 2008;33(7):1477‐502.

Mysiw W, Sandel M. The agitated brain injured patient. Part 2: Pathophysiology and treatment. Archives of Physical Medicine and Rehabilitation 1997;78(2):213‐20.

Poole N, Dougall D, Agrawal N. Pharmacotherapy for chronic cognitive impairment in traumatic brain injury. Cochrane Database of Systematic Reviews 2011, Issue 7. [DOI: 10.1002/14651858.CD009221]

Previc FH. Dopamine and the origins of human intelligence. Brain and Cognition 1999;41(3):299‐350.

Salazar AM, Warden DL, Schwab K, Spector J, Braverman S, Walter J, et al. Cognitive rehabilitation for traumatic brain injury: a randomized trial. Journal of the American Medical Association 2000;283(23):3075‐81.

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273(5):408‐12.

Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendation. Version 3.6 [updated October 2011]. The GRADE Working Group 2011.

Google Scholar

Silver JM, Hales RE, Yudofsky SC. Neuropsychiatric aspects of traumatic brain injury. In: S.C. Yudofsky, R.E. Hales editor(s). The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioural Neurosciences. 5th Edition. Washington, DC: American Psychiatric Publishing, Inc., 2008:595‐647.

Google Scholar

Tabaddor K, Mattis S, Zazula. Cognitive sequelae and recovery course after moderate and severe head injury. Neurosurgery 1984;14(6):701‐8.

Google Scholar

Teasdale TW, Engberg AW. Psychosocial consequences of stroke: a long‐term population‐based follow‐up. Brain Injury 2005;19(12):1049‐58.

Tenovuo OS. Cholinergic treatment of traumatic brain injury. Current Drug Therapy 2006;1(2):187‐209.

Thornhill S, Teasdale GM, Murray GD, McEwen J, Roy CW, Penny KI. Disability in young people and adults one year after head injury: prospective cohort study. British Medical Journal 2000;320(7250):1631‐5.

Van Woerkom TC, Teelken AW, Minderhous JM. Difference in neurotransmitter metabolism in frontotemporal‐lobe contusion and diffuse cerebral contusion. Lancet 1977;1(8015):812‐3.

Van Woerkom TC, Minderhoud JM. Pharmacologic interventions. Physical Medicine and Rehabilitation: Review 1990;4(3):447‐64.

Google Scholar

Whyte J, Nakase‐Richardson R, Hammond FM, McNamee S, Giacino JT, Kalmar K, et al. Functional outcomes in traumatic disorders of consciousness: 5‐year outcomes from the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems. Archives of Physical Medicine and Rehabilitation 2013;94(10):1855‐60.

Wilson BA. Management and remediation of memory problems in brain‐injured adults. The Handbook of Memory Disorders. 2nd Edition. John Wiley & Sons, 2002:655‐82.

Google Scholar

Zerbe RL, Rowe H, Enas GG, Wong D, Farid N, Lemberger L. Clinical pharmacology of tomoxetine, a potential antidepressant. Journal of Pharmacology and Experimental Therapeutics 1985;232(1):139‐43.

References to other published versions of this review

Ir a:

estudios incluidos
estudios excluidos
estudios en curso
otras referencias

Poole NA, Agrawal N. Cholinomimetic agents and neurocognitive impairment following head injury: a systematic review. Brain Injury 2008;22(7):519‐34.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos
estudios en curso

Jha 2008

Methods	Twelve week (first phase) single centre randomised placebo‐controlled cross‐over trial. Recruitment conducted from November 2002 to March 2005.
Participants	Fifty‐one males and females in the United States aged 16 to 65, at least one year post traumatic brain injury who required in‐patient rehabilitation. Experiencing fatigue or excessive daytime sleepiness, or both, which compromises optimal day time functioning.
Interventions	Treatment: Modafinil 100 mg daily for three days, then 100 mg twice daily for 11 days, followed by 200 mg twice daily for eight weeks. Followed by a four‐week washout period and then cross‐over. Dose reduction to 200 mg daily if non‐tolerance of 400 mg daily. Placebo: Placebo tablets with the same timings as for the treatment arm.
Outcomes	Medical Outcome Study 12‐Item Short Form Survey (SF‐12). Immediate Post Concussion Assessment Cognitive Testing (ImPACT): Computerised cognitive test battery assessing verbal memory, visual memory, visual motor speed and reaction time. Conners' Continuous Performance Test II (CPT‐II): Computerised test of vigilance developed for individuals with attention deficit hyperactivity disorder. Measures were administered at baseline, week four and week ten of treatment, repeated at week four and week ten following cross‐over. Attrition rates for each arm were reported. Number and type of adverse events for each arm were reported.
Funding	The study was supported by the US Department of Education, Office of Special Education and Rehabilitation Services, National Institute on Disability and Rehabilitation Research and Cephalon Inc.
Declarations of interest	None reported.
Notes	Adverse event data for phase 1 were provided by the study author.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation sequence.
Allocation concealment (selection bias)	Low risk	Pharmacy department responsible for maintaining study blinding, who administered modafinil or placebo according to the randomisation sequence.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and personnel blinded to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators, study coordinator, data collectors, analysts blinded to allocation.
Incomplete outcome data (attrition bias) All outcomes	High risk	Fifty‐one participants randomised, with only 49 included in the analysis. No reference to intention‐to‐treat analysis.
Selective reporting (reporting bias)	Low risk	Outcomes were reported as planned in the study protocol.
Other bias	Unclear risk	The primary outcome of the study investigated treatment of fatigue and not cognitive functioning.

Johansson 2012

Methods	Four week (first phase) single centre randomised placebo‐controlled cross‐over trial. Study dates not reported.
Participants	Twelve male and female participants aged 30 to 65, recruited via a local newspaper in Sweden or from the Department of Neurology at Sahlgrenska University Hospital in Gothenburg, six who had suffered a TBI and six stroke at least 12 months earlier who had pathological mental fatigue and had recovered from neurological symptoms.
Interventions	Treatment: Administered (−)‐OSU6162. Week 1: 30 mg daily; week 2: 60 mg daily; week 3 and 4: 90 mg daily in divided doses with individual variability. Followed by a four‐week cross‐over without a washout period. Placebo: Details of the administration of placebo were not described.
Outcomes	Trail Making Test A, B, C, D. Wechsler Adult Intelligence Scale digit symbol coding. Wechsler Adult Intelligence Scale digit span. F‐A‐S verbal fluency test.
Funding	The study was supported by the Arvid Carlsson Foundation and the Foundation for Neuropharmacological Research and Education.
Declarations of interest	None reported.
Notes	Data for TBI participants were provided by the study author.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	An insufficient description of the randomisation process was provided, limited to "randomisation was done externally".
Allocation concealment (selection bias)	Low risk	Allocation was done "externally" to ensure blinded randomisation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding was described as "both the participants and all study staff members were blinded. The code was broken only after all participants had terminated the study".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Allocation was not known at the point of assessment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The number of dropouts, and reasons, were reported.
Selective reporting (reporting bias)	Low risk	Outcomes were reported as planned in the study protocol.
Other bias	Unclear risk	The protocol planned for 25 participants compared to 12 in the study. The primary outcome of the study investigated treatment of fatigue and not cognitive functioning.

Ripley 2014

Methods	Two week (first phase) single centre randomised double‐blind placebo‐controlled cross‐over trial. Recruitment was completed in March 2014.
Participants	Sixty males and females in the United States aged 18 to 65, who had received inpatient rehabilitation following a moderate to severe traumatic brain injury at least one year earlier. Participants were included if attention dysfunction was present, indicated by a score of 4 or higher on the Adult ADHD Self‐Report Scale, or a score of 0.35 or higher on the Cognitive Failures Questionnaire (CFQ), or a score of 0.42 or higher on the Other CFQ.
Interventions	All participants received a two‐week placebo run‐in. Treatment: Atomoextine 40 mg twice daily for two weeks. Followed by a two‐week placebo washout period and then cross‐over. Placebo: Identical placebo tablets with the same timings as for the treatment arm.
Outcomes	Cognitive Drug Research (CDR) Computerized Cognitive Assessment System. Study secondary outcomes: CDR Continuity of Attention CDR Quality of Episodic Memory CDR Speed of Memory CDR Efficiency of Attention Stroop Colour and Word Test Adult ADHD Self‐Report Scale Neurobehavioural Functioning Inventory Attrition rates for each arm. Number and type of adverse events for each arm.
Funding	The study was supported by the Rocky Mountain Regional Brain Injury System (Grant number H133A070022), funded by an award from the US Department of Education’s National Institute on Disability and Rehabilitation Research. The study received investigator‐initiated support from Lilly Research Laboratories, who provided the active drug and placebo.
Declarations of interest	None reported.
Notes	Phase 1 data were provided by the study authors.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed “using a computer generated randomization sequence”.
Allocation concealment (selection bias)	Low risk	The “study physician and study coordinator enrolled participants and assigned study numbers sequentially as participants enrolled”. Pharmacy staff administered the randomisation protocol independently to study staff.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The study was described as “double‐blind”. The “randomization sequence was given to the pharmacy and no study staff had access to it”.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Allocation was not known at the point of assessment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The number of dropouts, and reasons, were reported. There were no dropouts during the first treatment phase which is relevant to this review.
Selective reporting (reporting bias)	Low risk	Outcomes were reported as planned in the study protocol.
Other bias	Low risk	None identified.

Silver 2006

Methods	Twelve‐week randomised placebo controlled study in 19 centres. Study dates not reported.
Participants	One hundred and fifty‐seven males and females in the United States aged 18 to 50. At least one year post head injury meeting ICD‐9 criteria for non‐penetrating head injury and DSM‐IV TR criteria for cognitive disorder NOS, dementia due to TBI or amnesic disorder due to TBI. Discrepancy of at least one standard deviation between current estimated intelligence measured by the Wechsler Adult Intelligence Scale 3rd Edition (WAIS‐III) information and vocabulary subsets and current attention or verbal functioning as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB) and Rapid Visual Information Processing (RVIP) A' subtest or the Hopkins Verbal Learning Test (HVLT) total Trials 1 through 3.
Interventions	Treatment: Rivastigmine 3 mg to 6 mg for 12 weeks. Commenced rivastigmine 1.5 mg twice daily, increased to 3 mg twice daily after a minimum of four weeks. Reduced to 3 mg daily if adverse effects experienced at 6 mg daily. Placebo: Administered a matching placebo.
Outcomes	Study primary outcomes (Administered at baseline, and weeks 4, 8 and 12): Cambridge Neuropsychological Test Automated Battery. Hopkins Verbal Learning Test, Rapid Visual Information Processing A' subtest. Study secondary outcomes (Administered at baseline and week 12): Controlled Oral Word Association. Wechsler Adult Intelligence Scale digit span. Wechsler Adult Intelligence Scale letter number sequencing. Trail Making tests Parts A and B. Neurobehavioral Functioning Inventory. Diener Satisfaction with Life Scale. Clinical Global Impression of Change. Attrition rates for each arm reported. Number and type of adverse event for each arm reported.
Funding	The study was supported by Novartis Pharmaceuticals Corporation.
Declarations of interest	Multiple authors listed as receiving honoraria from Novartis, two authors listed as employees of Novartis and one listed as a former employee of Novartis.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation was performed using "a validated system", however the system is not described.
Allocation concealment (selection bias)	Unclear risk	Method of allocation is not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as "double‐blind" with a "matching placebo".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Raters were blinded to the participant's treatment allocation".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis with last observation carried forward. Ten of 80 withdrew from the treatment arm, five due to adverse events and five due to other reasons not stated. Thirteen of 77 withdrew from the placebo arm, seven due to adverse events and six due to other reasons not stated.
Selective reporting (reporting bias)	Low risk	Study inclusion criteria and outcome measurement time scales varied from the protocol. The protocol planned to include participants aged 18 to 65, compared to 18 to 50 years in the study. Different cognitive tests to those proposed in the protocol were used. The protocol planned for treatment for 20 weeks, as opposed to 12 weeks in the study. These discrepancies would likely be balanced across both arms of the study.
Other bias	Low risk	None identified.

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Johansson 2015	No placebo control group.
León‐Carrión 2000	The length of time post TBI was not clearly defined.
Plenger 1996	The length of time post TBI was not clearly defined.
Schneider 1999	The length of time post TBI was not clearly defined.
Speech 1993	Phase one data was not reported and was unavailable from the study author.
Tenovuo 2009	Phase one data was not reported and was unavailable from the study author.

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

NCT01670526 2012

Trial name or title	Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI (RIVET)
Methods	Multi‐centre, randomised placebo‐controlled study.
Participants	Estimated 256 male and female outpatient veterans aged between 19 to 50, with a history of closed head trauma at least 12 months prior to enrolment. TBI classified as mild, with verbal memory deficits and subjective memory impairment.
Interventions	Treatment: Rivastigmine transdermal patch for 12 weeks. Control: Placebo comparator for 12 weeks.
Outcomes	Primary: Efficacy defined by comparing the proportion of responders in each group, with treatment response defined as at least a 5‐word improvement from baseline to 12 weeks on the Hopkins Verbal Learning Test ‐ Revised (HVLT‐R) total learning for Trials 1‐3. Secondary: Assessment of functional capacity, cognitive functioning, mood, quality of life, and safety measures.
Starting date	September 2012
Contact information	Rebekah Hardin, MHA (843) 740‐1592 ext 37 [email protected]
Notes

Data and analyses

Open in table viewer

Comparison 1. Modafinil vs placebo (4 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SF‐12 Physical Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐2.18 [‐6.34, 1.98]
Open in figure viewer Analysis 1.1 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 1 SF‐12 Physical.
2 SF‐12 Mental Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	1.95 [‐2.84, 6.74]
Open in figure viewer Analysis 1.2 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 2 SF‐12 Mental.
3 ImPACT verbal memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	1.42 [‐4.42, 7.26]
Open in figure viewer Analysis 1.3 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 3 ImPACT verbal memory composite.
4 ImPACT visual memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐6.52, 7.02]
Open in figure viewer Analysis 1.4 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 4 ImPACT visual memory composite.
5 ImPACT visual motor speed composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐3.45 [‐6.48, ‐0.42]
Open in figure viewer Analysis 1.5 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 5 ImPACT visual motor speed composite.
6 ImPACT reaction time composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.04, 0.08]
Open in figure viewer Analysis 1.6 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 6 ImPACT reaction time composite.
7 CCPT‐II No. of omissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	16.57 [‐3.59, 36.73]
Open in figure viewer Analysis 1.7 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 7 CCPT‐II No. of omissions.
8 CCPT‐II No. of commissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	2.00 [‐1.75, 5.75]
Open in figure viewer Analysis 1.8 Comparison 1 Modafinil vs placebo (4 weeks), Outcome 8 CCPT‐II No. of commissions.

Open in table viewer

Comparison 2. Modafinil vs placebo (10 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SF‐12 Physical Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐0.53 [‐5.46, 4.40]
Open in figure viewer Analysis 2.1 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 1 SF‐12 Physical.
2 SF‐12 Mental Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	0.41 [‐4.28, 5.10]
Open in figure viewer Analysis 2.2 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 2 SF‐12 Mental.
3 ImPACT verbal memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	4.11 [‐1.37, 9.59]
Open in figure viewer Analysis 2.3 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 3 ImPACT verbal memory composite.
4 ImPACT visual memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐1.61 [‐8.97, 5.75]
Open in figure viewer Analysis 2.4 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 4 ImPACT visual memory composite.
5 ImPACT visual motor speed composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐1.44 [‐4.61, 1.73]
Open in figure viewer Analysis 2.5 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 5 ImPACT visual motor speed composite.
6 ImPACT reaction time composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.08, 0.02]
Open in figure viewer Analysis 2.6 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 6 ImPACT reaction time composite .
7 CCPT‐II No. of omissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	15.67 [‐4.36, 35.70]
Open in figure viewer Analysis 2.7 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 7 CCPT‐II No. of omissions.
8 CCPT‐II No. of commissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	2.96 [‐0.47, 6.39]
Open in figure viewer Analysis 2.8 Comparison 2 Modafinil vs placebo (10 weeks), Outcome 8 CCPT‐II No. of commissions.

Open in table viewer

Comparison 3. (−)‐OSU6162 vs placebo (4 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Trail Making Test A (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	‐9.20 [‐12.19, ‐6.21]
Open in figure viewer Analysis 3.1 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 1 Trail Making Test A (seconds).
2 Trail Making Test B (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	‐6.20 [‐7.81, ‐4.59]
Open in figure viewer Analysis 3.2 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 2 Trail Making Test B (seconds).
3 Trail Making Test C (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	28.4 [‐11.39, 68.19]
Open in figure viewer Analysis 3.3 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 3 Trail Making Test C (seconds).
4 Trail Making Test D (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	53.5 [36.76, 70.24]
Open in figure viewer Analysis 3.4 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 4 Trail Making Test D (seconds).
5 WAIS‐III Digit Symbol Coding Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	8.6 [6.47, 10.73]
Open in figure viewer Analysis 3.5 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 5 WAIS‐III Digit Symbol Coding.
6 WAIS‐III Digit‐Span Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐5.17, 7.77]
Open in figure viewer Analysis 3.6 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 6 WAIS‐III Digit‐Span.
7 FAS Verbal Fluency (total words) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	‐10.63 [‐27.30, 6.04]
Open in figure viewer Analysis 3.7 Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 7 FAS Verbal Fluency (total words).

Open in table viewer

Comparison 4. Atomoxetine vs placebo (2 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CDR Power of Attention (Milliseconds) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	5.31 [‐66.81, 77.43]
Open in figure viewer Analysis 4.1 Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 1 CDR Power of Attention (Milliseconds).
2 CDR Continuity of Attention (% accuracy) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐1.94, 1.44]
Open in figure viewer Analysis 4.2 Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 2 CDR Continuity of Attention (% accuracy).
3 CDR Efficiency (COA/POA, % accuracy/millisecond) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.76 [‐3.10, 4.62]
Open in figure viewer Analysis 4.3 Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 3 CDR Efficiency (COA/POA, % accuracy/millisecond).
4 Stroop Interference Trial 4 Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.24 [‐2.27, 2.75]
Open in figure viewer Analysis 4.4 Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 4 Stroop Interference Trial 4.
5 Adult ADHD Self‐Report Scale (ASRS‐v1.1.) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐1.19 [‐5.63, 3.25]
Open in figure viewer Analysis 4.5 Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 5 Adult ADHD Self‐Report Scale (ASRS‐v1.1.).

Open in table viewer

Comparison 5. Rivastigmine vs placebo (12 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HVLT‐total word recall Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	0.21 [‐1.14, 1.56]
Open in figure viewer Analysis 5.1 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 1 HVLT‐total word recall.
2 HVLT‐delayed recall component retention, % Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	1.06 [‐5.66, 7.78]
Open in figure viewer Analysis 5.2 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 2 HVLT‐delayed recall component retention, %.
3 HVLT–recognition discriminant index Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.78, 0.66]
Open in figure viewer Analysis 5.3 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 3 HVLT–recognition discriminant index.
4 CANTAB RVIP’A Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.03, 0.00]
Open in figure viewer Analysis 5.4 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 4 CANTAB RVIP’A.
5 CANTAB–SWM, total errors Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	1.05 [‐5.85, 7.95]
Open in figure viewer Analysis 5.5 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 5 CANTAB–SWM, total errors.
6 CANTAB RVIP, mean latency, ms Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐44.54 [‐88.62, ‐0.46]
Open in figure viewer Analysis 5.6 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 6 CANTAB RVIP, mean latency, ms.
7 CANTAB‐RT, simple reaction time, ms Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐19.81 [‐59.23, 19.61]
Open in figure viewer Analysis 5.7 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 7 CANTAB‐RT, simple reaction time, ms.
8 CANTAB‐PAL, total errors Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐3.16 [‐10.75, 4.43]
Open in figure viewer Analysis 5.8 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 8 CANTAB‐PAL, total errors.
9 COWA–semantic association fluency Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.97, 1.51]
Open in figure viewer Analysis 5.9 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 9 COWA–semantic association fluency.
10 Trail Making Test A (seconds) Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐2.83 [‐7.38, 1.72]
Open in figure viewer Analysis 5.10 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 10 Trail Making Test A (seconds).
11 Trail Making Test B (seconds) Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	3.48 [‐6.31, 13.27]
Open in figure viewer Analysis 5.11 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 11 Trail Making Test B (seconds).
12 WAIS‐III‐DS scaled score Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐0.33, 0.77]
Open in figure viewer Analysis 5.12 Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 12 WAIS‐III‐DS scaled score.

Open in table viewer

Comparison 6. Acceptability of treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Modafinil vs placebo Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]
Open in figure viewer Analysis 6.1 Comparison 6 Acceptability of treatment, Outcome 1 Modafinil vs placebo.
2 Rivastigmine vs placebo Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.35, 1.59]
Open in figure viewer Analysis 6.2 Comparison 6 Acceptability of treatment, Outcome 2 Rivastigmine vs placebo.
3 (‐)‐OSU6162 vs placebo Show forest plot	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
Open in figure viewer Analysis 6.3 Comparison 6 Acceptability of treatment, Outcome 3 (‐)‐OSU6162 vs placebo.
4 Atomoxetine vs placebo Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
Open in figure viewer Analysis 6.4 Comparison 6 Acceptability of treatment, Outcome 4 Atomoxetine vs placebo.

Open in table viewer

Comparison 7. Modafinil vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dizziness Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	3.56 [0.43, 29.66]
Open in figure viewer Analysis 7.1 Comparison 7 Modafinil vs placebo adverse events, Outcome 1 Dizziness.
2 Dysgeusia Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]
Open in figure viewer Analysis 7.2 Comparison 7 Modafinil vs placebo adverse events, Outcome 2 Dysgeusia.
3 Dyspepsia Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]
Open in figure viewer Analysis 7.3 Comparison 7 Modafinil vs placebo adverse events, Outcome 3 Dyspepsia.
4 Fatigue Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.44 [0.56, 35.41]
Open in figure viewer Analysis 7.4 Comparison 7 Modafinil vs placebo adverse events, Outcome 4 Fatigue.
5 Insomnia Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.59, 11.99]
Open in figure viewer Analysis 7.5 Comparison 7 Modafinil vs placebo adverse events, Outcome 5 Insomnia.
6 Memory impairment Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]
Open in figure viewer Analysis 7.6 Comparison 7 Modafinil vs placebo adverse events, Outcome 6 Memory impairment.
7 Nasopharyngitis Show forest plot	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 3.59]
Open in figure viewer Analysis 7.7 Comparison 7 Modafinil vs placebo adverse events, Outcome 7 Nasopharyngitis.
8 Nausea Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.30, 23.96]
Open in figure viewer Analysis 7.8 Comparison 7 Modafinil vs placebo adverse events, Outcome 8 Nausea.
9 Weight loss Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]
Open in figure viewer Analysis 7.9 Comparison 7 Modafinil vs placebo adverse events, Outcome 9 Weight loss.
10 Unknown Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]
Open in figure viewer Analysis 7.10 Comparison 7 Modafinil vs placebo adverse events, Outcome 10 Unknown.

Open in table viewer

Comparison 8. (−)‐OSU6162 vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Nausea Show forest plot	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.01, 8.62]
Open in figure viewer Analysis 8.1 Comparison 8 (−)‐OSU6162 vs placebo adverse events, Outcome 1 Nausea.

Open in table viewer

Comparison 9. Atomoxetine vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Headache Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.85]
Open in figure viewer Analysis 9.1 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 1 Headache.
2 Dry mouth Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	5.78 [0.27, 126.14]
Open in figure viewer Analysis 9.2 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 2 Dry mouth.
3 Globus pharyngeus Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.3 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 3 Globus pharyngeus.
4 Hypertension Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.4 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 4 Hypertension.
5 Insomnia Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	5.78 [0.27, 126.14]
Open in figure viewer Analysis 9.5 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 5 Insomnia.
6 Irritable bowl Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.6 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 6 Irritable bowl.
7 Loss of appetite Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.7 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 7 Loss of appetite.
8 Nasal congestion Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.8 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 8 Nasal congestion.
9 Shoulder pain Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.9 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 9 Shoulder pain.
10 Urinary retention Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]
Open in figure viewer Analysis 9.10 Comparison 9 Atomoxetine vs placebo adverse events, Outcome 10 Urinary retention.

Open in table viewer

Comparison 10. Rivastigmine vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anxiety Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	8.67 [0.47, 158.32]
Open in figure viewer Analysis 10.1 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 1 Anxiety.
2 Arthralgia Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [0.36, 10.21]
Open in figure viewer Analysis 10.2 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 2 Arthralgia.
3 Diarrhoea Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	2.41 [0.48, 12.03]
Open in figure viewer Analysis 10.3 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 3 Diarrhoea.
4 Dizziness Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	7.7 [0.99, 60.12]
Open in figure viewer Analysis 10.4 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 4 Dizziness.
5 Headache Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.35, 2.10]
Open in figure viewer Analysis 10.5 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 5 Headache.
6 Nausea Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [1.29, 7.22]
Open in figure viewer Analysis 10.6 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 6 Nausea.
7 Upper respiratory tract infection Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [0.70, 6.74]
Open in figure viewer Analysis 10.7 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 7 Upper respiratory tract infection.
8 Vomiting Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	7.7 [0.99, 60.12]
Open in figure viewer Analysis 10.8 Comparison 10 Rivastigmine vs placebo adverse events, Outcome 8 Vomiting.

Figure 1

Study flow diagram.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.1

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 1 SF‐12 Physical.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 2 SF‐12 Mental.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 3 ImPACT verbal memory composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.4

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 4 ImPACT visual memory composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.5

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 5 ImPACT visual motor speed composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.6

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 6 ImPACT reaction time composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.7

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 7 CCPT‐II No. of omissions.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.8

Comparison 1 Modafinil vs placebo (4 weeks), Outcome 8 CCPT‐II No. of commissions.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.1

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 1 SF‐12 Physical.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.2

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 2 SF‐12 Mental.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.3

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 3 ImPACT verbal memory composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.4

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 4 ImPACT visual memory composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.5

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 5 ImPACT visual motor speed composite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.6

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 6 ImPACT reaction time composite .

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.7

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 7 CCPT‐II No. of omissions.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.8

Comparison 2 Modafinil vs placebo (10 weeks), Outcome 8 CCPT‐II No. of commissions.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.1

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 1 Trail Making Test A (seconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.2

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 2 Trail Making Test B (seconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.3

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 3 Trail Making Test C (seconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.4

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 4 Trail Making Test D (seconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.5

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 5 WAIS‐III Digit Symbol Coding.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.6

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 6 WAIS‐III Digit‐Span.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.7

Comparison 3 (−)‐OSU6162 vs placebo (4 weeks), Outcome 7 FAS Verbal Fluency (total words).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.1

Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 1 CDR Power of Attention (Milliseconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.2

Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 2 CDR Continuity of Attention (% accuracy).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.3

Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 3 CDR Efficiency (COA/POA, % accuracy/millisecond).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.4

Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 4 Stroop Interference Trial 4.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.5

Comparison 4 Atomoxetine vs placebo (2 weeks), Outcome 5 Adult ADHD Self‐Report Scale (ASRS‐v1.1.).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.1

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 1 HVLT‐total word recall.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.2

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 2 HVLT‐delayed recall component retention, %.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.3

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 3 HVLT–recognition discriminant index.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.4

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 4 CANTAB RVIP’A.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.5

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 5 CANTAB–SWM, total errors.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.6

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 6 CANTAB RVIP, mean latency, ms.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.7

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 7 CANTAB‐RT, simple reaction time, ms.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.8

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 8 CANTAB‐PAL, total errors.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.9

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 9 COWA–semantic association fluency.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.10

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 10 Trail Making Test A (seconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.11

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 11 Trail Making Test B (seconds).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.12

Comparison 5 Rivastigmine vs placebo (12 weeks), Outcome 12 WAIS‐III‐DS scaled score.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.1

Comparison 6 Acceptability of treatment, Outcome 1 Modafinil vs placebo.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.2

Comparison 6 Acceptability of treatment, Outcome 2 Rivastigmine vs placebo.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.3

Comparison 6 Acceptability of treatment, Outcome 3 (‐)‐OSU6162 vs placebo.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.4

Comparison 6 Acceptability of treatment, Outcome 4 Atomoxetine vs placebo.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.1

Comparison 7 Modafinil vs placebo adverse events, Outcome 1 Dizziness.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.2

Comparison 7 Modafinil vs placebo adverse events, Outcome 2 Dysgeusia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.3

Comparison 7 Modafinil vs placebo adverse events, Outcome 3 Dyspepsia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.4

Comparison 7 Modafinil vs placebo adverse events, Outcome 4 Fatigue.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.5

Comparison 7 Modafinil vs placebo adverse events, Outcome 5 Insomnia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.6

Comparison 7 Modafinil vs placebo adverse events, Outcome 6 Memory impairment.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.7

Comparison 7 Modafinil vs placebo adverse events, Outcome 7 Nasopharyngitis.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.8

Comparison 7 Modafinil vs placebo adverse events, Outcome 8 Nausea.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.9

Comparison 7 Modafinil vs placebo adverse events, Outcome 9 Weight loss.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.10

Comparison 7 Modafinil vs placebo adverse events, Outcome 10 Unknown.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 8.1

Comparison 8 (−)‐OSU6162 vs placebo adverse events, Outcome 1 Nausea.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.1

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 1 Headache.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.2

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 2 Dry mouth.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.3

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 3 Globus pharyngeus.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.4

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 4 Hypertension.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.5

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 5 Insomnia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.6

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 6 Irritable bowl.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.7

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 7 Loss of appetite.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.8

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 8 Nasal congestion.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.9

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 9 Shoulder pain.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 9.10

Comparison 9 Atomoxetine vs placebo adverse events, Outcome 10 Urinary retention.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.1

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 1 Anxiety.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.2

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 2 Arthralgia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.3

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 3 Diarrhoea.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.4

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 4 Dizziness.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.5

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 5 Headache.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.6

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 6 Nausea.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.7

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 7 Upper respiratory tract infection.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 10.8

Comparison 10 Rivastigmine vs placebo adverse events, Outcome 8 Vomiting.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Summary of findings for the main comparison. Pharmacological agents compared to placebo for chronic cognitive impairment in traumatic brain injury

Modafanil, (−)‐OSU6162, atomoxetine or rivastigmine compared to placebo for chronic cognitive impairment in traumatic brain injury
Patient or population: Participants with chronic cognitive impairment in traumatic brain injury Settings: Inpatient or community Intervention: Drug treatment Comparison: Placebo (2 to 10 weeks)
Outcomes	Effect of drug treatment for people with cognitive impairment in traumatic brain injury	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Cognitive performance on psychometric tests	The majority of sub‐tests showed no difference between treatment and placebo. Superiority over placebo was shown in one measure in Silver 2006 and several measures in Johansson 2012 and Johansson 2015. However, interpretation of these findings are cautioned.	See comment.	274 (4 studies)	⊕⊝⊝⊝ very low^1,2,3	Data synthesis was not possible due to the heterogeneity of studies.
Clinical global improvement	A single study reported no difference between treatment and placebo.	See comment.	51 (1 study)	⊕⊕⊝⊝ low^1,3	Data synthesis was not possible as only one study reported a measure on clinical global improvement.
Acceptability	No differences between treatment and placebo were found.	See comment.	274(4 studies)	⊕⊝⊝⊝ very low^1,2,3	Data synthesis was not possible due to the heterogeneity of studies.
Safety	More nausea was reported in participants receiving rivastigmine than placebo (Silver 2006). No other differences were found.	See comment.	274 (4 studies)	⊕⊝⊝⊝ very low^1,2,3	Data synthesis was not possible due to the heterogeneity of studies.
Mortality	No deaths were reported by any study.	Not estimable.	274 (4 studies)	‐
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ downgraded one level due to serious indirectness, as two of four studies did not investigate cognitive impairment as a primary outcome ² downgraded one level due to serious inconsistency, due to wide variance of point estimates. ³ downgraded one level due to serious imprecision, as the total population size was less than 400.

Summary of findings for the main comparison. Pharmacological agents compared to placebo for chronic cognitive impairment in traumatic brain injury

Ir a la tabla de la revisión

Comparison 1. Modafinil vs placebo (4 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SF‐12 Physical Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐2.18 [‐6.34, 1.98]

2 SF‐12 Mental Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	1.95 [‐2.84, 6.74]

3 ImPACT verbal memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	1.42 [‐4.42, 7.26]

4 ImPACT visual memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐6.52, 7.02]

5 ImPACT visual motor speed composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐3.45 [‐6.48, ‐0.42]

6 ImPACT reaction time composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.04, 0.08]

7 CCPT‐II No. of omissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	16.57 [‐3.59, 36.73]

8 CCPT‐II No. of commissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	2.00 [‐1.75, 5.75]

Comparison 1. Modafinil vs placebo (4 weeks)

Ir a la tabla de la revisión

Comparison 2. Modafinil vs placebo (10 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SF‐12 Physical Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐0.53 [‐5.46, 4.40]

2 SF‐12 Mental Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	0.41 [‐4.28, 5.10]

3 ImPACT verbal memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	4.11 [‐1.37, 9.59]

4 ImPACT visual memory composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐1.61 [‐8.97, 5.75]

5 ImPACT visual motor speed composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐1.44 [‐4.61, 1.73]

6 ImPACT reaction time composite Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.08, 0.02]

7 CCPT‐II No. of omissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	15.67 [‐4.36, 35.70]

8 CCPT‐II No. of commissions Show forest plot	1	51	Mean Difference (IV, Fixed, 95% CI)	2.96 [‐0.47, 6.39]

Comparison 2. Modafinil vs placebo (10 weeks)

Ir a la tabla de la revisión

Comparison 3. (−)‐OSU6162 vs placebo (4 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Trail Making Test A (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	‐9.20 [‐12.19, ‐6.21]

2 Trail Making Test B (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	‐6.20 [‐7.81, ‐4.59]

3 Trail Making Test C (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	28.4 [‐11.39, 68.19]

4 Trail Making Test D (seconds) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	53.5 [36.76, 70.24]

5 WAIS‐III Digit Symbol Coding Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	8.6 [6.47, 10.73]

6 WAIS‐III Digit‐Span Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐5.17, 7.77]

7 FAS Verbal Fluency (total words) Show forest plot	1	6	Mean Difference (IV, Fixed, 95% CI)	‐10.63 [‐27.30, 6.04]

Comparison 3. (−)‐OSU6162 vs placebo (4 weeks)

Ir a la tabla de la revisión

Comparison 4. Atomoxetine vs placebo (2 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CDR Power of Attention (Milliseconds) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	5.31 [‐66.81, 77.43]

2 CDR Continuity of Attention (% accuracy) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐1.94, 1.44]

3 CDR Efficiency (COA/POA, % accuracy/millisecond) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.76 [‐3.10, 4.62]

4 Stroop Interference Trial 4 Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.24 [‐2.27, 2.75]

5 Adult ADHD Self‐Report Scale (ASRS‐v1.1.) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐1.19 [‐5.63, 3.25]

Comparison 4. Atomoxetine vs placebo (2 weeks)

Ir a la tabla de la revisión

Comparison 5. Rivastigmine vs placebo (12 weeks)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HVLT‐total word recall Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	0.21 [‐1.14, 1.56]

2 HVLT‐delayed recall component retention, % Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	1.06 [‐5.66, 7.78]

3 HVLT–recognition discriminant index Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.78, 0.66]

4 CANTAB RVIP’A Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.03, 0.00]

5 CANTAB–SWM, total errors Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	1.05 [‐5.85, 7.95]

6 CANTAB RVIP, mean latency, ms Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐44.54 [‐88.62, ‐0.46]

7 CANTAB‐RT, simple reaction time, ms Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐19.81 [‐59.23, 19.61]

8 CANTAB‐PAL, total errors Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐3.16 [‐10.75, 4.43]

9 COWA–semantic association fluency Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.97, 1.51]

10 Trail Making Test A (seconds) Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	‐2.83 [‐7.38, 1.72]

11 Trail Making Test B (seconds) Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	3.48 [‐6.31, 13.27]

12 WAIS‐III‐DS scaled score Show forest plot	1	157	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐0.33, 0.77]

Comparison 5. Rivastigmine vs placebo (12 weeks)

Ir a la tabla de la revisión

Comparison 6. Acceptability of treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Modafinil vs placebo Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]

2 Rivastigmine vs placebo Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.35, 1.59]

3 (‐)‐OSU6162 vs placebo Show forest plot	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

4 Atomoxetine vs placebo Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 6. Acceptability of treatment

Ir a la tabla de la revisión

Comparison 7. Modafinil vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dizziness Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	3.56 [0.43, 29.66]

2 Dysgeusia Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]

3 Dyspepsia Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]

4 Fatigue Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.44 [0.56, 35.41]

5 Insomnia Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.59, 11.99]

6 Memory impairment Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]

7 Nasopharyngitis Show forest plot	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 3.59]

8 Nausea Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.30, 23.96]

9 Weight loss Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]

10 Unknown Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	4.46 [0.22, 88.61]

Comparison 7. Modafinil vs placebo adverse events

Ir a la tabla de la revisión

Comparison 8. (−)‐OSU6162 vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Nausea Show forest plot	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.01, 8.62]

Comparison 8. (−)‐OSU6162 vs placebo adverse events

Ir a la tabla de la revisión

Comparison 9. Atomoxetine vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Headache Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.85]

2 Dry mouth Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	5.78 [0.27, 126.14]

3 Globus pharyngeus Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

4 Hypertension Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

5 Insomnia Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	5.78 [0.27, 126.14]

6 Irritable bowl Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

7 Loss of appetite Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

8 Nasal congestion Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

9 Shoulder pain Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

10 Urinary retention Show forest plot	1	56	Odds Ratio (M‐H, Fixed, 95% CI)	3.34 [0.13, 85.56]

Comparison 9. Atomoxetine vs placebo adverse events

Ir a la tabla de la revisión

Comparison 10. Rivastigmine vs placebo adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anxiety Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	8.67 [0.47, 158.32]

2 Arthralgia Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [0.36, 10.21]

3 Diarrhoea Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	2.41 [0.48, 12.03]

4 Dizziness Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	7.7 [0.99, 60.12]

5 Headache Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.35, 2.10]

6 Nausea Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [1.29, 7.22]

7 Upper respiratory tract infection Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [0.70, 6.74]

8 Vomiting Show forest plot	1	157	Risk Ratio (M‐H, Fixed, 95% CI)	7.7 [0.99, 60.12]

Comparison 10. Rivastigmine vs placebo adverse events

Ir a la tabla de la revisión

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Referencias

References to studies included in this review

Jha 2008 {published and unpublished data}

Johansson 2012 {unpublished data only}

Ripley 2014 {unpublished data only}

Silver 2006 {published data only}

References to studies excluded from this review

Johansson 2015 {unpublished data only}

León‐Carrión 2000 {published data only}

Plenger 1996 {published data only}

Schneider 1999 {published data only}

Speech 1993 {published data only}

Tenovuo 2009 {published data only}

References to ongoing studies

NCT01670526 2012 {published and unpublished data}

Additional references

Adams 1991

Aharon‐Peretz 2007

Arciniegas 1999

Bernstein 1999

Brooks 1976

Brown 1994

Burstein 2011

Carlsson 2011

Chalmers 1983

Cooper 1991a

Cooper 1991b

Cooper 1991c

DH

Fleminger 2005

Gentry 1988

Giacobini 2002

Griffin 2003

Hayes 1989

Heilman 1993

Higgins 2011

Himanen 2006

Jennett & Bond 1975

Kay 1993

Koponen 2002

Lahti 2007

Lippert‐Gruner 2006

Lu 2012

McDowell 1997

Minzenberg 2008

Mysiw 1997

Poole 2011

Previc 1999

Salazar 2000

Schulz 1995

Schünemann 2011

Silver 2008

Tabaddor 1984

Teasdale 2005

Tenovuo 2006

Thornhill 2000

Van Woerkom 1977

Van Woerkom 1990

Whyte 2013

Wilson 2002

Zerbe 1985

References to other published versions of this review

Poole 2008

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

Copiar o descargar referencia

Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso