Pharmacological interventions for traumatic brain injury

Traumatic brain injury is common in North America and has dramatic and wide-ranging effects on survivors’ quality of life. Those who survive traumatic brain injury may experience anxiety, agitation, memory impairments, and behavioral changes. When managing the immediate and long-term consequences of such injuries, clinicians have many pharmacological options, including psychostimulants, antidepressants, antiparkinsonian agents, and anticonvulsants. These and other agents can play a role in managing the neuropsychiatric, neurocognitive, and neurobehavioral sequelae of injury to the brain.


Psychostimulants, antidepressants, and other agents may speed the recovery of patients suffering from the functional deficits that follow an insult to the brain.


Traumatic brain injury (TBI) is commonly defined as an insult to the brain from an external force that causes temporary or permanent impairment in functional, psychosocial, or physical abilities.1 It is a significant cause of morbidity and mortality, and the leading cause of death and disability among young adults. 

Common causes of TBI include motor vehicle accidents, falls, sports injuries, and violence,[1] and it is recog­nized increasingly in war zone injury.[2] In the US, approximately 2 million people will sustain a TBI each year, one-quarter of whom will require hospitalization, leading to a conservative estimate of direct and indirect costs of $50 billion to $100 billion annually.[3

With advances in the management of head trauma, an increasing number of patients are surviving with residual neurological impairments. A National Institute of Health panel estimates that 2.5 to 6.5 million Americans currently live with TBI-related disabilities.[4]

The effective treatment of TBI requires input from multiple disciplines and professions starting at the time of injury and continuing through the rehabilitation phase. 

Despite the prevalence and cost of TBI-related disabilities there is a paucity of literature reviewing modern approaches to pharmacotherapy. There is, however, growing evidence that medications may speed recovery by enhancing some neurological functions without impact­ing others. 

Pharmacotherapy is in­creasingly being used in both the subacute (less than 1 month post-TBI) and chronic (more than 1 month post-TBI) phases. 

Disabilities arising from TBI that have a direct impact on functioning and rehabilitative potential can be broadly classified into four main categories: decreased level of consciousness (LOC), and neuropsychiatric, neurocognitive, and neurobehavioral sequelae.5-8 Decreased level of consciousness refers to a diverse range of clinical states including coma, vegetative states, akinetic mutism, and locked-in states.

Neuropsychiatric symp­toms may present as mood disorders, posttraumatic stress disorder, and personality changes characterized by disinhibition and egocentricity. Neurocognitive injuries vary, but most frequently involve impaired attention, memory, and executive functioning. 

Neurobehavioral deficits distinct from neuropsychiatric sequelae may take the form of irritability, hyperexcitability, nervousness, disinhibition, poor impulse control, restlessness, and aggression, with aggression and agitation seen in as many as 30% of brain-injured patients.[5-8]

Depending on the location of in­jury, damage can occur to a variety of neurotransmitter networks critical to cognitive processes. Investigation has focused on the loss of dopaminergic neurons that regulate executive functioning, as well as deficits in norepinephrine and acetylcholine, which limit attention—a critical function for effective rehabilitation.[9

Fortunately, a number of pharmacological interventions show promise in helping patients cope with these losses and deficits.

Although insufficient evidence exists to establish guidelines for optimal pharmocotherapy, medications may be used to support recovery. Examples are shown in the accompanying Table, which summarizes the pharmacological approaches discussed in more detail below. 

When problematic TBI symptoms are identified, clinicians can use this information to determine pharmacological options and integrate them with nonpharmacological options such as physical therapy, occupational therapy, physiatry, and the patient’s support network.

Planning a pharmacological intervention strategy
The decision to use pharmacological intervention should be the result of multidisciplinary collaboration and made with the patient or his or her substitute decision maker. Goals of therapy should be clarified, and outcomes and adverse events should be reliably tracked, particularly so medications that are ineffective or cause adverse events can be discontinued and unnecessary polypharmacy can be avoided. 

Selecting the most appropriate agent requires careful analysis of the neurological disabilities present, the nature of the underlying lesion, and the time elapsed since the injury.

Psychostimulants
Psychostimulants such as methylpheni­date are most commonly used to treat attention deficit hyperactivity disorder (ADHD), a condition that involves problems with executive functioning and can be characterized as similar to brain injury both in terms of symptoms and neurotransmitter aberrations.[10

Although the complete mechanism of action of methylphenidate remains unknown, this agent is thought to bind dopamine transporters, thereby blocking reuptake and increasing extracellular dopamine levels, particularly in the frontal cortex.[11] It is also thought to increase norepinephrine and serotonin levels. 

In the majority of studies, methylphenidate has been administered  twice daily, either at a fixed dose of 10 to 15 mg or at a dose of 0.3 mg/kg.[12-15

In the acute phase after a TBI, methylphenidate-treated patients dem­onstrated better attention, concentration, and performance on motor memory tasks at 1 month, but these benefits did not persist at 3 months. Thus, it has been suggested that while methyl­phenidate may shorten recovery time, it does not change morbidity.[12]

In the chronic phase after a TBI, patients have reported improvements in mood, work performance, and alertness, with more limited evidence suggesting an improvement of fluency and selective attention. 

The impact of methylphenidate on chronic attention is more ambiguous: one study suggests improvement in long-term processing speed and attention to tasks but not increased sustained attention or decreased susceptibility to distraction.[12

Two separate studies have suggested methylphenidate is effective in the treatment of agitation and sei­zures,[16,17] while another demonstrated no neurobehavioral benefit.[18

Despite the accumulation of controlled clinical trials, there is no consensus on the use of stimulants in treating TBI-induced impairments in arousal and motor activity. 

It should be noted that one recent review concluded “at present there is insufficient evidence to support routine use of methylphenidate or other amphetamines to promote recovery from TBI,”[19] while another review noted that at least 10 clinical trials have demonstrated a role for methylpheni­date in both adult and pediatric brain injury patients suffering from neurocognitive deficits, particularly in attention, memory, cognitive processing, and speech.[20

Methylphenidate has a quick onset of action and relatively benign side effect profile, and we believe it to be useful in both the acute and chronic phase of TBI.

Antidepressants
Despite potentially severe consequenc­es, post-TBI psychiatric sequelae are underdiagnosed and undertreated. Fortunately, current evidence suggests that antidepressants can be used to manage both neuropsychiatric and additional neurological deficits persisting from brain injury.

Selective serotonin reuptake inhi­bitors (SSRIs) have been found useful in treating behavioral syndromes in TBI patients, particularly in the subacute stages of recovery[21] but also in chronic settings. 

The majority of studies suggest that SSRIs improve neurobehavioral, neurocognitive, and neuropsychiatric deficits, specifically agitation, depression, psychomotor retardation, and recent memory loss; however, most data originates from nonrandomized trials.

Sertraline administered at an average dose of 100 mg daily for 8 weeks has been found to be beneficial for agitation, depressed mood, and deficits in psychomotor speed and recent memory; shorter treatment durations have demonstrated no benefit.[21

Similarly, 60 mg daily of fluoxetine for 3 months was shown to be effective in the treatment of obsessive-compulsive disorder caused by brain injury.[22] Finally, paroxetine or citalopram, at a dose of 10 to 40 mg daily, was shown by another study to be equally effective in the treatment of pathological crying.[23] None of the re­viewed studies addressed neurocognitive deficits.

The highest concentration of serotonergic and adrenergic fibres is located near the frontal lobes, the most common site of traumatic contusion.[24

Consequently, these fibres are commonly injured in TBI, suggesting that newer antidepressants with effects on both norepinephrine and serotonin, such as mirtazapine and venlafaxine, may also be effective in the treatment of TBI sequelae; however, clinical data with these agents in TBI is lacking. 

Similarly, bupropion increases both dopamine and norepinephrine levels and is a weak inhibitor of serotonin reuptake. At 150 mg daily, this agent has been useful in treating restlessness.[25]

Antiparkinsonian drugs
The antiparkinsonian drugs amantadine, bromocriptine, and levodopa combined with carbidopa (e.g., Sine­met) have varied mechanisms of action, but all ultimately serve to increase dopamine levels in the brain.

Amantadine acts presynaptically to enhance dopamine release or inhibit its reuptake, and can act postsynaptically to increase the number, or alter the configuration of, dopamine re­ceptors.[26] It is also a noncompetitive NMDA receptor antagonist and may provide protection against possible glutamate-mediated excitotoxicity in the context of TBI.[27

Bromocriptine is a dopamine receptor agonist affecting primarily D2 receptors and to a lesser extent D1 receptors.[28] The use of levodopa and carbidopa in combination directly increases dopamine levels: levodopa becomes dopamine once de­carboxylated, while carbidopa inhibits L-amino decarboxylase, allowing levodopa to reach the central nervous system.[28]

Multiple studies of amantadine at a dose of 100 to 300 mg daily have suggested its effectiveness in both the acute and chronic care phases after TBI, particularly in diffuse, frontal, or right-sided brain injury.

Currently, the evidence suggests neurocognitive or neurobehavioral deficits, particularly cognition difficulties and agitation, are primary indications for amantadine use.[26,29,30

Amantadine-treated patients demonstrated improvements in motivation; decreased level of apathy; increased attention, concentration, and alertness; improved executive functioning; decreased processing time; reduced agitation, distractibility, fatigue, aggression, and anxiety. 

In addition, patients treated with amantadine demonstrated changes in outcome LOC, specifically improved arousal and LOC as measured by the Glasgow Coma Scale. Interestingly, one study also suggested decreased mortality.[31] To date, no study has shown an improvement in memory.

Three case reports using 5 to 45 mg of bromocriptine daily,[32] and one study using a combination of 100 mg of bromocriptine with 100 mg of ephedrine,[33] showed improvement in akinetic mutism, while another study using 5 mg of bromocriptine combined with sensory stimulation led to improvements in patients with vegetative or minimal consciousness.[34

The evidence is similarly limited for levidopa and carbidopa medications where nonrandomized studies suggest that they might be useful in the chronic phase of TBI with diffuse injury and persistent vegetative state.[35

Combining agents has also been tried in one study that found improvements in neuropsychiatric deficits with the daily administration of 25 mg/200 mg of levodopa/carbidopa three times daily, 250 mg of amantadine, and 5 mg of bromocriptine twice daily.[36]

Anticonvulsants
Anticonvulsants have been used with varying results for treating symptoms of TBI. Valproic acid, for example, enhances inhibitory control mediated by the neurotransmitter GABA, thereby promoting general central nervous system stabilization, but findings thus far have been mixed. 

Investigations utilizing 600 to 2250 mg of valproic acid daily (resulting in serum levels of 40 to 100 µg/mL), have demonstrated positive neurocognitive effects, in­cluding improved recent memory and problem-solving, as well as ameliorating neuropsychiatric and neuro­behavioral symptoms such as depression, mania, destructive and aggressive behavior, restlessness, disinhibition, impulsivity, lability, and alertness.[37-41

Conversely, one control­led trial found valproic acid negatively impacted decision-making speed, and another suggested an increased mortality rate with valproic acid use.[37-41]

Other agents
Modafinil is a vigilance-promoting drug commonly used to treat narcolepsy and idiopathic hypersomnia, illnesses that can present with symptoms similar to those seen in TBI: excessive daytime sleepiness, inattention, and decreased ability to perform social activities. 

The precise mechanism of action remains unknown, although it is believed that modafinil can inhibit GABA or increase glutamate levels in the nondopaminergic anterior hypothalamus, hippocampus, and amygdale.[42,43

Two studies that investigated the role of modafinil in chronic TBI showed an improvement in neurocognitive deficits, specifically memory and attention, as well as improving daytime somnolence at doses between 100 and 400 mg.[44,45]

Four randomized control trials examining the use of beta-blockers, specifically propranolol and pindolol, have demonstrated beneficial effects on neurobehavioral symptoms of ag­gression and agitation in both the chronic and subacute phase. This class of drugs deserves further attention for the management of both neuropsychiatric and neurobehavioral sequelae of TBI.[46

Neuroleptics are being used in­creasingly in the setting of delirium, and one might consider using them in an attempt to allow the brain to recalibrate neurotransmitter levels. However, it should be noted that there is some evidence that dopamine blockade may negatively affect recovery.[47,48

There are also a number of animal studies examining drugs that have the potential to adversely affect brain recovery following TBI. These studies typically use a stroke model, so generalizing to TBI may not be possible. 

Nevertheless, the evidence currently does not support the use of neuro­leptics, benzodiazepines, phen­y­toin, prazosin, trazodone, and similar agents because of their potential adverse effect on recovery, presumably through the impacts they have on neurotransmitters such as dopamine, norepinephrine, or GABA.[49-51]

Preliminary evidence suggests cho­linesterase inhibitors such as don­epezil may improve long-term cognitive outcomes, particularly in domains such as memory and attention when administered early, and further in­vestigation with these agents is also warranted.[52,53]

Finally, antiandrogenic medications, such as estrogen and medroxyprogesterone, may have a role to play in reducing inappropriate sexual be­havior in patients with TBI. In a case study and one small trial, these drugs demonstrated effectiveness.[54]

Summary
The nature of TBI sequelae, whether psychiatric, cognitive, or behavioral, is poorly understood. Likewise, the use of pharmacological interventions to improve symptoms, function, and outcome is still under development. 

There are, however, a number of agents that inspire optimism. When treating neurological deficits medically, there is evidence to support the tailored use of these agents for particular TBI clinical scenarios. The timing and nature of symptoms, along with wheth­er agents are administered in the acute or chronic phase after TBI, are all relevant factors for determining proper use.

With insufficient evidence to establish guidelines for optimal treatment, care must be taken when choosing pharmacological interventions for TBI. 

If the decision is made to use medications to promote TBI recovery or treat its attendant disabilities, clinicians should thoroughly document the goals of pharmacotherapy and closely monitor for side effects. Future studies will undoubtedly add to the clinician’s armamentarium for the care of TBI patients.

Competing interests
None declared.


References

1. Bruns J Jr, Hauser WA. The epidemiology of traumatic brain injury: A review. Epilepsia 2003;44:2-10.
2. Okie S. Traumatic brain injury in the war zone. N Engl J Med 2005;352:2043-2047.
3. Thurman DJ, Alverson C, Dunn KA, et al. Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil 14 1999;14:602-615.
4. Woo BH, Nesathurai S (eds). The rehabilitation of patients with traumatic brain injury. Malden, MA: Blackwell Science; 2000:5-12.
5. Bricolo A. Prolonged posttraumatic coma, In: Vinken PJ, Bruyn GW (eds). Handbook of clinical neurology Amsterdam: Elsevier; 1976:699-755.
6. O’Dell MW, Riggs RV. Management of the minimally responsive patient. In: Horn LJ (ed). Medical rehabilitation of traumatic brain injury. Philadelphia: Hanley and Belfus; 1996:103-131.
7. Salmond CH, Sahakian BJ. Cognitive outcome in traumatic brain injury survivors. Curr Opin Crit Care 2005;11:111-116.
8. Hellawell DJ, Taylor RT, Pentland B. Cognitive and psychosocial outcome following moderate or severe traumatic brain injury. Brain Inj 1999;13:489-504.
9. Arciniegas DB, The cholinergic hypothesis of cognitive impairment caused by traumatic brain injury. Curr Psychiatry Rep 2003;5:391-399.
10. Evans RW, Gualtieri CT. Psychostimulant pharmacology in traumatic brain injury. J Head Trauma Rehabil 1987;2:29-33.
11. Challman T, Lipsky J. Methylphenidate: Its pharmacology and uses. Mayo Clin Proc 2000;75:711-721.
12. Whyte J, Hart T, Schuster K, et al. Effects of methylphenidate on attentional function after traumatic brain injury. Am J Phys Med Rehabil 1997;76:440-450.
13. Kaelin C, Cifu D, Matthies B. Methyl­phenidate effect on attention deficit in the acutely brain-injured adult. Arch Phys Med Rehabil 1996;77:6-10.
14. Speech T, Rao S, Osmon D, et al. A double blind controlled study of methylphen­idate treatment in closed head injury. Brain Inj 1993;7:333-338.
15. Plenger P, Dixon E, Castillo R, et al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil 1996;77:536-540.
16. Mooney G, Haas L. Effect of methyl­phen­i­date on brain injury-related anger. Arch Phys Med Rehabil 1993;74:153-160.
17. Wroblewski B, Leary J, Phelan A, et al. Methylphenidate and seizure frequency in brain injured patients with seizure disorders. J Clin Psychiatry 1992;53:86-89.
18. Evans R, Gualtieri T, Patterson D. Treatment of chronic closed head injury with psychostimulant drugs: A controlled case study and an appropriate evaluation procedure. J Nerv Ment Dis 1987;175:110.
19. Forsyth R, Jayamoni B. Noradrenergic agonists for acute traumatic brain injury. Cochrane Database Syst Rev 2003;(1):CD003984.
20. Siddall OM, Use of methylphedinate in traumatic brain injury. Ann Pharmacother 2005;39:1309-1313.
21. Meythaler J, Lawrence D, Devivo M, et al. Sertraline to improve arousal and alertness in severe traumatic brain injury secondary to motor vehicle crashes. Brain Inj 2000;15:321-331.
22. Stengler-Wenzke K, Muller U. Fluoxetine for OCD after brain injury. Am J Psychiatry 2002;159:872.
23. Muller U, Mural T, Bauer-Wittmund T, et al. Paroxetine versus citalopram treatment of pathological crying after brain injury. Brain Inj 1999;13:808-811.
24. De Marchi R, Bansal V, Hung A, et al. Review of awakening agents. Can J Neurol Sci 2005;32:4-17.
25. Teng C, Bhalerao S, Lee A, et al. The use of buproprion in the treatment of restlessness after a traumatic brain injury. Brain Inj 2001;15:463-467.
26. Schneider W, Drew-Cates J, Wong T, et al. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: An initial double-blind placebo-controlled study. Brain Injury 1999;13:863-872.
27. Kraus M, Maki P. The combined use of amantadine and l-dopa/carbidopa in the treatment of chronic brain injury. Brain Inj 1997;11:455-460.
28. Zafonte R, Lexell J, Cullen N. Possible applications for dopaminergic agents following traumatic brain injury: Part 1. J Head Trauma Rehabil 2000;15:1179-1182.
29. Meythaler J, Brunner R, Johnson A, et al. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: A pilot double-blind randomized trial. J Head Trauma Rehabil 2002;31:300-313.
30. Zafonte R, Watanabe T, Mann N. Amantadine: A potential treatment for the minimally conscious state. Brain Inj 1998;12:617-621.
31. Saniova B, Drobny M, Kneslova L, et al. The outcome of patients with severe head injuries treated with amantadine sulphate. J Neur Transm 2004;111:511-514.
32. Crismon M, Childs A, Wilcox R, et al. The effect of bromocriptine on speech dysfunction in patients with diffuse brain injury (akinetic mutism). Clin Neuropharmacol 1988;11:462-466.
33. Anderson B. Relief of akinetic mutism from obstructive hydrocephalus using bromocriptine and ephedrine. J Neurosurg 1992;76:152-155.
34. Passler M, Riggs R. Positive outcomes in traumatic brain injury-vegetative state: Patients treated with bromocriptine. Arch Phys Med Rehabil 2001;82:311-315.
35. Haig A, Ruess J. Recovery from vegetative state of six months’ duration associated with Sinemet (levodopa/carbidopa). Arch Phys Med Rehabil 1990;71:1081-1082.
36. Karli D, Burke D, Kim H, et al. Effects of dopaminergic combination therapy for frontal lobe dysfunction in traumatic brain injury rehabilitation. Brain Inj 1999;13:63-68.
37. Wroblewski B, Joseph A, Kupfer J, et al. Effectiveness of valproic acid on destructive and aggressive behaviours in pa­tients with acquired brain injury. Brain Inj 1997;11:37-47.
38. Massagli T. Neurobehavioral effects of phenytoin, carbamazepine, and valproic acid: Implications for use in traumatic brain injury. Arch Phys Med and Rehabil 1991;72:219-225.
39. Dikmen S, Machamer J, Winn H, et al. Neuropsychological effects of valproate in traumatic brain injury. Neurology 2000;54:895-902.
40. Chatham-Showalter P, Kimmel DN. Agitated symptom response to divalproex following acute brain injury. J Neuropsychiatry Clin Neurosci 2000;12:395-397.
41. Kim E, Humaran T. Divalproex in the management of neuropsychiatric complications of remote acquired brain injury. J Neuropsychiatry Clin Neurosci 2002;14:202-205.
42. Lin J, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos im­muno­cytochemistry in the cat. Proc Natl Acad Sci U S A 1996;93:14128-14133.
43. Ferraro L, Antonelli T, Tanganelli S. The vigilance promoting drug modafinil in­creases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: Prevention by local GABAA receptor blockade. Neuropsychopharmacology 1999;20:346-356.
44. Saletu B, Saletu M, Grunberger J, et al. Treatment of the alcoholic organic brain syndrome: Double-blind, placebo-controlled clinical, psychometric and electroencephalographic mapping studies with modafinil. Neuropsychobiology 1993;27:26-39.
45. Teitelman E. Off-label uses of modafinil. Am J Psychiatry 2001;158:1341.
46. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev 2003;(1):CD003299.
47. Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol and experience interact to affect the rate of recovery after motor cortex injury. Science 1982;217:855-857.
48. Goldstein LB. Common drugs may influence motor recovery after stroke. Neurology 1995;45:865-872.
49. Schallert T, Hernandez T, Barth T. Recovery of function after brain damage: Severe and chronic disruption by diaze­pam. Brain Res 1986;379:104-111.
50. Brailowsky S, Knight RT, Efron R. Phenytoin increases the severity of cortical hemiplegia in rats. Brain Res 1986;376:71-77.
51. Goldstein LB. Influence of common drugs and related factors on stroke outcome. Curr Opin Neurol 1997;10:52-57.
52. Zhang L, Plotkin RC, Wang G, et al. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil 2004;85:1050-1055.
53. Walker W, Seel R, Gibellato M, et al. The effects of donepezil on traumatic brain injury acute rehabilitation outcomes. Brain Inj 2004;18:739-750.
54. Levy M, Berson A, Cook T, et al. Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation 2005;20:279-306.


This article has been peer reviewed.

Dr Talsky is a psychiatry resident at the University of Toronto. Ms Pacione is a senior medical student at the University of Toronto. Dr Shaw is a family practice resident at St. Michael’s Hospital in Toronto. Dr Was­serman is a psychiatry resident at the University of Toronto. Mr Lenny is a senior medical student at the University of Toronto. Mr Verma is a senior medical student at the University of Toronto. Ms Hurwitz is a bachelor of science student at the University of Western Ontario in London. Dr Waxman is a psychiatry resident at the University of Toronto. Dr Morgan is a psychiatry resident at the University of Toronto. Dr Bhalerao is a staff psychiatrist at St. Michael’s Hospital.

Aaron Talsky, MD,, Laura R. Pacione, MSc,, Tammy Shaw, MD,, Lori Wasserman, MD,, Adam Lenny, BSc, BA,, Amol Verma, BSc,, Gillian Hurwitz,, Robyn Waxman, MD,, Andrew Morgan, MD,, Shree Bhalerao, MD, FRCPC,. Pharmacological interventions for traumatic brain injury. BCMJ, Vol. 53, No. 1, January, February, 2011, Page(s) 26-31 - Clinical Articles.



Above is the information needed to cite this article in your paper or presentation. The International Committee of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.

About the ICMJE and citation styles

The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.

An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.

BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:

  • Only the first three authors are listed, followed by "et al."
  • There is no period after the journal name.
  • Page numbers are not abbreviated.


For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org

BCMJ Guidelines for Authors

Leave a Reply