Source

Search strategy

Hits retrieved

1. ALOIS (www.medicine.ox.ac.uk/alois)

[last searched 30 December 2014]

Keyword search: traumatic OR TBI OR "brain injury" OR "brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries"

Dec 2011: 41

Feb 2013: 9

Jan 2014: 1

Dec 2014: 1

2. MEDLINE In‐process and other non‐indexed citations and MEDLINE 1950‐present (Ovid SP)

[last searched 30 December 2014]

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. randomized.ab.

4. placebo.ab.

5. drug therapy.fs.

6. randomly.ab.

7. trial.ab.

8. groups.ab.

9. or/1‐8

10. (animals not (humans and animals)).sh.

11. 9 not 10

12. ("drug treatment*" or "pharmacological treatment*" or pharmacotherapy).ti,ab.

13. Cholinergic Agents/

14. (cholinomimetic or cholinergic*).ti,ab.

15. (arecolin* or arecholin*).ti,ab.

16. (meclofenoxat* or meclophenoxat*).ti,ab.

17. (centrofenoxin* or centrophenoxin*).ti,ab.

18. ("ANP 235" or "EN 1627").ti,ab.

19. (deanol* or demanol* or "CR 121" or "RS 86").ti,ab.

20. (physostigmin* or fysostigmin* or lecithin* or lecitin*).ti,ab.

21. (choline or cholin or coline).ti,ab.

22. (tacrin* or takrin*).ti,ab.

23. (tetrahydroaminoacridin* or tetrahydroaminacrin* or "CI 970" or THA or THAA).ti,ab.

24. ("7‐methoxyacridin*" or "7‐metoxyacridin*" or methoxytacrin* or metoxytacrin* or metoxytakrin* or methoxycrin* or metoxycrin* or MEOTA).ti,ab.

25. (ipidacrin* or amiridin* or NIK247 or "NIK 247").ti,ab.

26. (donepezil* or E2020 or "E 2020" or galanthamin* or galantamin* or "CGP 37267").ti,ab.

27. (rivastigmin* or ENA713 or "ENA 713" or "212 713").ti,ab.

28. (eptastigmin* or heptylstigmin* or heptylphysostigmin* or heptylfysostigmin*).ti,ab.

29. ("L 693 487" or MF201 or "MF 201" or metrifonat* or metriphonat*).ti,ab.

30. (trichlorfon* or trichlorphon* or trichlorfen* or trichlorphen* or "L 1359" or "Bay a 9826" or "Bay 1 1359").ti,ab.

31. (xanomelin* or "LY 246708" or "FG 10232" or cevimelin* or AF102B or "AF 102B'").ti,ab.

32. ("FKS 508" or "SND 5008" or SNK508 or SNI2011).ti,ab.

33. or/12‐32

34. Antidepressive Agents/

35. Antidepressive Agents, Second‐Generation/

36. Antidepressive Agents, Tricyclic/

37. (Amesergide or amineptine hydrochloride or amitriptyline).ti,ab.

38. (amoxapine or "benactyzine hydrochloride" or brofaromine or "bupropion hydrochloride" or "butriptyline hydrochloride").ti,ab.

39. (cianopramine or "citalopram hydrobromide" or clomipramine or "clorgyline hydrochloride" or clovcxamine).ti,ab.

40. ("demexiptiline hydrochloride" or "desipramine hydrochloride" or "dibenzepin hydrochloride" or "dimetacrine tartrate" or "dothiepin hydrochloride" or "doxepin hydrochloride" or "etoperidone hydrochloride").ti,ab.

41. (femoxetine or "fezolamine fumarate" or "fluoxetine hydrochloride" or "fluvoxamine maleate").ti,ab.

42. (ifoxetine or "imipramine hydrochloride" or "iprindole hydrochloride" or "iproniazid phosphate" or isocarboxazid or levoprotiline or "lofepramine hydrochloride" or "maprotiline hydrochloride").ti,ab.

43. (medifoxamine or "melitracen hydrochloride" or "metapramine fumarate" or "mianserin hydrochloride" or milnacipran or "minapri hydrochloride" or mirtazapine).ti,ab.

44. (moclobemide or nefazodone hydrochloride or nialamide or nomifensine maleate or nortriptyline hydrochloride or opipramol hydrochloride or oxaflozane hydrochloride or oxaprotiline hydrochloride or oxitriptan).ti,ab.

45. (paroxetine hydrochloride or phenelzine sulphate or pirlindole or propizepine hydrochloride or protriptyline hydrochloride).ti,ab.

46. (quinupramine or rolipram or rubidium chloride or sertraline hydrochloride or setiptiline or sibutramine or teniloxazine or tianepine sodium or tofenacin hydrochloride).ti,ab.

47. (oloxatone or tranylcypromine sulphate or trazadone hydrochloride or trimipramine or tryptophan or venlafaxine hydrochloride or viloxazine hydrochloride or viqualine or zimelidine hydrochloride).ti,ab.

48. or/34‐47

49. Antipsychotic Agents/

50. (clozapine or olanzapine or pirenzepine or sertindole or imidazoles or indoles).ti,ab.

51. (risperidone or quetiapine or ziprasidone or piperazines or thiazoles or sulpiride or zotepine or zotepine or amisulpride).ti,ab.

52. (sulpride or deniban or solian or socian or sulamid or DAN or abilify or OPC or clozaril or alemoxan or elcrit or froidir or klozapol).ti,ab.

53. (leponex or olasek or ziprexa or zyprexa or seroquel or risperdal or belivon or risperin).ti,ab.

54. (rispolept or rispolin or neripros or rizodal or serdolect or serlect or zoleptil or aiglonyl or alimoral or ansium).ti,ab.

55. (arminol or betamaks or calmoflorine or championyl or darleton or depex or depreal or desisulpid or digton or dixibon).ti,ab.

56. (dobren or dogmatil or dogmatyl or dolmatil or dresent or eclorion or eglonyl or enimon or equilid or esipride or fardalan).ti,ab.

57. (fidelan or intrasil or lebopride or mariastel or meresa or mirbanil or neogama or neoride or noneston or norestran).ti,ab.

58. (normum or nufarol or nylipark or omaha or omiryl or ozedeprin or paratil or prosulpin or psicocen or quastil).ti,ab.

59. (quiridil or restful or stamoneurol or sulp or sulparex or sulpiphar or sulpir or sulpirid or sulpiryd or sulpitil or sulpivert).ti,ab.

60. (sulpril or suprium or synedil or tepavil or tepazepam or valirem or neogamma or zemorcon or zeprid or zymocomb).ti,ab.

61. (geodon or zoleptil or Benperidol or anquil or benperidols or frenactil or glianimon or psichoben or Chlorpromazine).ti,ab.

62. (aminazins or ancholactil or biscasil or bukatel or chlorazin or chlorpromazin or clordezalin or fenactil or fleksin).ti,ab.

63. (kloproman or klorproman or largactil or largatrex or megaphen or Nevropromazine or Plegomazin or Propaphenin).ti,ab.

64. (prozil or prozin or repazine or solidon or tardyl or thorazine or zuledin or Flupentixol or depixol or fluanxel or fluanxol).ti,ab.

65. (Fluphenazine or anatensol or cardilac or cenilene or dapotum or decafen or decazate or decentan or eutimox).ti,ab.

66. (fludecate or flufenazin or lyogen or lyoridin or lyorodin or mirenil or modecate or moditen or omca or pacinol or permitil).ti,ab.

67. (prolixin or prolongatum or sevinol or siqualone or fludecasin or Haloperidol or alased or aloperidin or avant).ti,ab.

68. (bioperidolo or buteridol or cereen or decaldol or decanoate or dozic or duraperidol or fortunan or haldol or haloneural).ti,ab.

69. (haloper or haloperin or norodol or novo‐peridol or peridol or sedaperidol or serenace or serenelfi or sevium or sigaperidol).ti,ab.

70. (sylador or vesadol or vesalium or zafrionil or levomepromazine or methotrimeprazine or levium or levomepromazin).ti,ab.

71. (levoprome or levozin or neurocil or norzinan or novo‐meprazine or nozinan or sinogan or tisercin or tisercinetta).ti,ab.

72. (veractil or Pericyazine or neulactil or perphenazine or decentan or peratsin or perdenasin or terfluoperazine or trilafon).ti,ab.

73. (trilafan or triptafen or fentazin or Pimozide or antalon or norofren or orap or pirium or Prochlorperazine).ti,ab.

74. (buccastem or bukatel or chlorperazinum or compazine or cotrazine or emetiral or klometil or mitil or nu‐prochlor).ti,ab.

75. (prochlorperazin or scripto‐metic or stemetil or tementil or trinigrin or ultrazac or ultrazinol or vertigon or Promazine).ti,ab.

76. (prazine or promazin or protactyl or prozyl or sinophenin or sparine or talofen or Thioridazine or aldazine or elperil).ti,ab.

77. (flaracantyl or mallorol or mefurine or meleril or mellaril or melleretten or mellerettes or melleril or orsanil or ridazine).ti,ab.

78. (stalleril or thioridazin or tirodil or visergil or Trifluperazine or discimer or eskazine or foille or iremo or jatroneural).ti,ab.

79. (jatrosom or modalina or oxyperazine or parmodalin or parstelin or sedofren or sporalon or stelabid or stelazine).ti,ab.

80. (stelbid or stelium or stilizan or terfluoperazine or terflurazine or terfluzin or terfluzine or trifluoperazin or trisedyl).ti,ab.

81. (Pipotiazine or lonseren or piportil or piportyl or Zuclopenthixol or ciatyl or cisordinol or clopixol or sordinol).ti,ab.

82. or/49‐81

83. (amantadine or bromocriptine or mazindol or pergolide or dopamine agonist).ti,ab.

84. (amphetamine or d‐amphetamine or dexamphetamine or dextroamphetamine or methamphetamine or Methylphenidate or Modafinil or adrafinil or provigil).ti,ab.

85. (melatonin or N‐ACETYL‐5‐METHOXYTRYPTAMINE or atomoxetine or memanthine).ti,ab.

86. or/83‐85

87. Brain Injuries/

88. Brain Concussion/

89. Brain Hemorrhage, Traumatic/

90. Brain Injury, Chronic/

91. Diffuse Axonal Injury/

92. "brain injur*".ti,ab.

93. (TBI or TBIs).ti,ab.

94. ("hypoxic brain damage" or "diffuse axonal injur*" or DAI or DAIs).ti,ab.

95. "head injur*".ti,ab.

96. (brain adj2 trauma*).ti,ab.

97. (head adj2 trauma*).ti,ab.

98. concussion.ti,ab.

99. "brain contusion".ti,ab.

100. 33 or 48 or 82 or 86

101. or/87‐99

102. 100 and 101

103. 11 and 102

Dec 2011:

652

Feb 2013: 95

Jan 2014: 36

Dec 2014: 98

3. EMBASE

1980‐2011 week 45 (Ovid SP)

[last searched 30 December 2014]

1. "traumatic brain injur*".ti,ab.

2. (TBI or TBIs).ti,ab.

3. ("hypoxic brain damage" or "diffuse axonal injur*" or DAI or DAIs).ti,ab.

4. (brain adj2 trauma*).ti,ab.

5. (head adj2 trauma*).ti,ab.

6. concussion.ti,ab.

7. "brain contusion".ti,ab.

8. exp *traumatic brain injury/

9. or/1‐8

10. randomly.ab.

11. RCT.ti,ab.

12. clinical trial/

13. randomi?ed.ab.

14. placebo*.ti,ab.

15. groups.ab.

16. "double‐blind*".ti,ab.

17. or/10‐16

18. 9 and 17

Dec 2011: 1199

Feb 2013: 367

Jan 2014: 461

Dec 2014: 478

4. PSYCINFO

1806‐November week 3 2011 (Ovid SP)

[last searched 30 December 2014]

1. traumatic brain injury/

2. (TBI or TBIs).ti,ab.

3. ("hypoxic brain damage" or "diffuse axonal injur*" or DAI or DAIs).ti,ab.

4. "head injur*".ti,ab.

5. (brain adj2 trauma*).ti,ab.

6. (head adj2 trauma*).ti,ab.

7. concussion.ti,ab.

8. "brain contusion".ti,ab.

9. or/1‐8

10. randomi?ed.ab.

11. placebo*.ti,ab.

12. "double‐blind*".ti,ab.

13. randomly.ab.

14. "single‐blind*".ti,ab.

15. RCT.ti,ab.

16. or/10‐15

17. 9 and 16

Dec 2011: 430

Feb 2013: 157

Jan 2014: 84

Dec 2014: 117

5. CINAHL (EBSCOhost)

[last searched 30 December 2014]

S1 TX "traumatic brain injur*" 

S2 (MM "Brain Injuries") 

S3 TX "hypoxic brain damage" OR "diffuse axonal injur*" 

S4 TX "brain contusion"

S5 TX "brain trauma*" 

S6 TX "head trauma*" 

S7 TX TBI OR TBIs 

S8 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7

S9 (MH "Randomized Controlled Trials") 

S10 TX placebo* 

S11 TX randomly 

S12 TX "double‐blind*" OR "single‐blind*"

S13 S9 OR S10 OR S11 OR S12

S8 AND S13

Dec 2011: 255

Feb 2013: 70

Jan 2014: 46

Dec 2014: 69

6. Web of Science (1945‐present) (via ISI Web of Science)

[last searched 30 December 2014]

Topic=("traumatic brain injury" OR TBI OR TBIs) AND Topic=(randomly OR randomised OR randomized OR RCT) NOT Title=(mice OR mouse OR rat OR rats OR animal OR model)

Timespan=All Years. Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH.

Lemmatization=On  

Dec 2011: 1395

Feb 2013: 596

Jan 2014: 411

Dec 2014: 233

7. LILACS (BIREME)

[last searched 30 December 2014]

traumatic brain injury [Words] and random or RCT or randomised OR randomized OR trial OR placebo OR groups [Words]

Dec 2011: 16

Feb 2013: 5

Jan 2014: 0

Dec 2014: 0

8. CENTRAL (The Cochrane Library)

[last searched 30 December 2014]

#1 MeSH descriptor Brain Injuries explode all trees

#2 TBI OR TBIs

#3 "hypoxic brain damage" OR "diffuse axonal injur*"

#4 "head injur*"

#5 brain N/2 trauma*

#6 head N/2 trauma*

#7 "brain contusion"

#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)

Dec 2011: 963

Feb 2013: 67

Jan 2014: 15

Dec 2014: 57

9. Clinicaltrials.gov (www.clinicaltrials.gov)

[last searched 30 December 2014]

Advanced search: Condition: (Traumatic brain injury OR TBI OR TBIs OR brain contusion OR concussion) AND Intervention studies

Dec 2011: 255

Feb 2013: 64

Jan 2014: 8

Dec 2014: 2

10. ICTRP Search Portal (http://apps.who.int/trialsearch) [includes: Australian New Zealand Clinical Trials Registry; ClinicalTrilas.gov; ISRCTN; Chinese Clinical Trial Registry; Clinical Trials Registry – India; Clinical Research Information Service – Republic of Korea; German Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; Pan African Clinical Trial Registry; Sri Lanka Clinical Trials Registry; The Netherlands National Trial Register]

[last searched 30 December 2014]

Advanced search: Condition: (Traumatic brain injury OR TBI OR TBIs OR brain contusion OR concussion)

Dec 2011: 364

Feb 2013: 73

Jan 2014: 0

Dec 2014: 2

TOTAL before de‐duplication and assessment based on title and abstract screening

Dec 2011: 5582

Feb 2013: 1503

Jan 2014: 1062

Dec 2014: 1053

TOTAL: 9200

TOTAL after de‐duplication and assessment based on title and abstract screening

 Dec 2011: 438

Feb 2013: 142

Jan 2014: 71

Dec 2014: 24

TOTAL: 675

Unit of analyses issues

In any studies utilising a cross‐over design, only data from the first treatment phase after randomisation will be eligible for inclusion. In the case that numerous eligible studies take repeated observations of outcomes then time frames that reflect short,medium and long term follow‐up will be selected. Time frames will be defined as short term if at six weeks or less, medium term between six and 24 weeks, while long term studies will run for six months or more. If repeated observations are not a significant issue then the longest follow‐up will be selected for each study.

Assessment of heterogeneity

Heterogeneity to be tested using a standard Chi² statistic with a P = 0.1 being considered significant and quantified using the I² statistic. If there is evidence of heterogeneity of the treatment effect between trials then a random‐effects model will be used. If heterogeneity is too great (that is I² > 75%) then meta‐analysis will not be possible.

Assessment of reporting biases

To minimize the potential for publication bias, study authors, pharmaceutical companies and experts will be contacted to assist in the identification of unpublished studies. Furthermore, authors of identified studies will be contacted to enquire about duplication of studies and outcome reporting bias. Unpublished studies will be included in the meta‐analysis and the methodology and potential
for bias assessed using the same criteria as outlined above (see: ’Assessment of risk of bias in included studies’).

The intervention effect estimates from each study will be plotted against a measure of each study’s size or precision to create a funnel plot. If enough studies are identified (usually > 10) then the asymmetry can be assessed statistically (Begg and Mazumdar 1994), otherwise the funnel plot will be cautiously interpreted with the limitations of this method explicitly stated in the discussion.

Data synthesis

The review authors expect the studies to employ a wide range of tools assessing the same cognitive function and so meta‐analysis will utilize the standardised mean difference approach, standardising
the mean differences to a single scale. Differences in the direction of scales measuring the same outcome will be dealt with by multiplying by −1 to ensure all scales point are in the same direction. As usual, a study’s weight will be calculated using the standard deviation and sample size. A summary (pooled) intervention effect estimate will then be calculated as a weighted average of the intervention effects estimated in the individual studies, as described in the Cochrane Handbook, section 9.4.2.

Depending upon whether heterogeneity of results is identified, we will decide whether a fixed‐effect or a random‐effects model is used for meta‐analysis. In either case the inverse variance method
will be used.

The duration of the trials may vary considerably. If the range is considered too great to combine all trials into one meta‐analysis the data can be divided into smaller time frames and a separate meta analysis conducted for each period. Some trials may contribute data to more than one time period if multiple assessments have been made.

Pharmacotherapeutic interventions will be combined depending on the general class of drug (for example antidepressants). Subsequent subgroup analyses will focus on the neurotransmitter systems
affected by the intervention (for example serotonergic). Some pharmacotherapies may be included in more than one analysis if they are known to significantly affect multiple neurotransmitter systems. For example, duloxetine would be included in the serotonergic and adrenergic analyses. Standard texts on psychopharmacology and manufacturers’ information will be consulted to establish the pharmacodynamic properties of each agent. The formation of subgroups will be conducted once the search has been performed but before the outcomes have been extracted.

Subgroup analysis and investigation of heterogeneity

If statistical heterogeneity is identified then we will adopt the strategies recommended in the Cochrane Handbook, section 9.5.3. We will evaluate possible reasons for the heterogeneity by
assessing subgroups of trials: (i) difference in quality of trial, and (ii) severity of TBI.We will compare outcomes in those with mild TBI against those who suffered moderate to severe injury. Mild should be defined as Glasgow coma scale (GCS) greater than or equal to 13 with no penetrating injury.

Sensitivity analysis

Issues suitable for sensitivity analysis will be identified during the review process. If a particular decision appears to affect the findings then we will attempt to understand this and perhaps gain further
information from the authors of the original studies. Sensitivity analyses will be presented in table format and will inform the interpretation of the review’s findings.