Neurobehavioral Sequelae of Traumatic Brain InjuryPublished on Psychiatric Times(http://www.psychiatrictimes.com)

Neurobehavioral Sequelae of Traumatic Brain InjuryNews [1] | December 01, 2005 | Psychotic Affective Disorders [2], Mania [3], Major DepressiveDisorder [4], Neuropsychiatry [5], Addiction [6], Alcohol Abuse [7], Bipolar Disorder [8]By Shawn J. Kile, MD [9], NeedsFixing [10], Steven Sugden, MD [11], Celia H. Chang, MD [12], MarkE. Servis, MD [13], and Donald M. Hilty, MD [14]

traumatic brain injury, memory impairment, depression, neurobehavioral disorders

Recognition and early, accurate diagnosis of neurobehavioral TBI sequelae are important in reducingthe severity of postinjury symptoms. Because the neuropathology of TBI is diffuse and affects manyareas of the brain, a multiplicity of neurobehavioral symptoms is common after TBI. This makesstudy of the post-TBI population challenging and may be the reason for the relatively few studiesabout treating neurobehavioral symptoms after TBI.Although the following classification breaks down the manifestations of TBI according to psychiatricsymptom dimensions that have an intuitive correlation with specific psychiatric interventions, atypical patient may require a multimedication intervention to treat symptoms on various dimensions.On the other hand, after reviewing the following reasonable treatment options, a knowledgeablephysician may choose a medication that targets multiple neurobehavioral sequelae of TBI. However,medical management represents only one facet of the treatment of TBI; optimal treatment often willalso require cognitive rehabilitation, behavioral training, counseling, and other individualizedtherapeutic modalities.Cognitive Dysfunction after TBIMemory impairment Memory impairment is a common problem after TBI. The sensitivity of thehippocampus to physiologic stress and the mesial temporal predisposition to injury caused by thesphenoidal bony protuberances probably play a role.Acetylcholinesterase inhibitors have demonstrated promising results in the treatment of memorydysfunction after TBI. Donepezil (Aricept, Eisai/Pfizer) has been the most-studiedacetylcholinesterase inhibitor. Zhang and colleagues1 conducted a prospective randomizedcontrolled study of donepezil in brain-injured patients in which significant improvements wereachieved during the treatment phases on both memory and concentration measures. Several othernonrandomized studies have evaluated cognitive impairment secondary to TBI and the open-labeluse of donepezil.2-7 These studies also support the finding that donezepil improves overall memoryand attention.Diminished alertness, apathy, and amotivation Diminished alertness, apathy, and lack of motivationare common symptoms, particularly after diffuse axonal injury and bifrontal lobe injury. Patientsoften will not seek treatment themselves; however, family members will usually bring the patient infor evaluation because of a decline in function. Patients even may present as abulic.Amantadine (Symmetrel, Endo) is a dopaminergic medication that has been studied as a treatmentfor patients with TBI. It was initially proposed as a treatment because the frontal lobes are rich indopaminergic neurons. Therefore, maximizing dopamine function in patients with bifrontal injurymay result in improved function.A prospective randomized controlled study, conducted by Meythaler and colleagues,8 investigatedthe use of amantadine in patients with TBI and concluded that amantadine therapy was associatedwith a consistent trend toward improved neurorecovery with functional outcome measures. Otherstudies have demonstrated that amantadine specifically improves alertness, initiation, andmotivation in patients with TBI.9-11

Decreased processing speed and distractibility Impaired processing speed and inattention arecommon symptoms after TBI and are probably attributed to the disconnection effects of diffuseaxonal injury. Several prospective randomized controlled studies showed that treatment withmethylphenidate improved processing speed and inattention in patients with TBI.12-15

Affective Symptoms after TBIDepression Symptoms of depression include depressed mood, inability to experience pleasure,changes in sleep, changes in appetite, decreased energy, decreased concentration, hopelessness,

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Neurobehavioral Sequelae of Traumatic Brain InjuryPublished on Psychiatric Times(http://www.psychiatrictimes.com)

and suicidal thoughts. These symptoms can lead to significant impairment of function and evenmortality, if not addressed.Depression is probably the most commonly encountered disorder after TBI and is most likely causedby disruption of multiple neurotransmitter homeostasis. Selective serotonin reuptake inhibitors(SSRIs)--specifically sertraline (Zoloft, Pfizer)--have been studied for the treatment of depressionafter TBI and have been found to be effective.16-18 Although there is a lack of studies specificallyinvestigating treatment of depression after TBI with this class of medications, the dual serotonergicand noradrenergic agents venlafaxine (Effexor, Wyeth) and duloxetine (Cymbalta, Eli Lilly) arereasonable alternative choices.Bupropion (Wellbutrin, GlaxoSmithKline) is another treatment option, especially in a depressedpatient who has significant anergia or apathy.19 Because of their anticholinergic effects, which willfurther impair cognitive function and increase the risk of delirium, tricyclic antidepressants should beavoided in those patients with TBI in whom cognitive dysfunction and/or delirium is a concern.Bipolar symptoms Bipolar symptoms include cycles of depressive and manic symptoms. Manicsymptoms include elevated mood, increased energy, decreased need for sleep, pressured speech,and impulsive behaviors. Variants of pure unipolar mania, as well as the opposite extreme of rapidcycling-type bipolar symptoms, can be observed in patients with TBI. Some reports suggest thatthese novel bipolar symptoms may correlate with temporal polar injury.20,21 Treatment withmood-stabilizing antiepileptic drugs has been shown to be effective in such patients.22

Of the antiepileptics, valproate (Depacon, Abbott) and divalproex sodium (Depakote, Abbott) havebeen most studied and have been reported to be effective in treating post-traumatic bipolarsymptoms.23-25 Carbamazepine (Tegretol, Novartis) also has been reported to be effective in treatingbipolar symptoms in patients with TBI.26,27

Although not specifically investigated for use in patients with TBI who have bipolar symptoms,lamotrigine (Lamictal, GlaxoSmithKline) is another reasonable treatment option that has been usedfor managing behavioral symptoms in TBI. Atypical antipsychotics may be another treatment option,especially in bipolar patients who have psychotic features.Lithium carbonate should be avoided in patients with TBI. It lowers the seizure threshold, has thepotential for neurotoxicity, and has a low therapeutic index. Furthermore, the monitoring required incognitively impaired patients contributes to nonadherence.Anxiety Symptoms after TBIAnxiety syndromes, specifically acute stress disorder, post-traumatic stress disorder (PTSD), panicdisorder, generalized anxiety disorder, and obsessive-compulsive disorder, have been reported afterTBI. Anxiety symptoms may be attributed to trauma of the amygdala, which, like the hippocampus,is prone to injury because of its mesial temporal location.Limited data exist regarding the effectiveness of psychopharmacologic agents for the treatment ofanxiety disorders in patients with TBI; however, case reports support the use of SSRIs andvenlafaxine.28,29 Benzodiazepines generally should be avoided in patients with TBI because ofpotential further cognitive dysfunction as well as behavioral disinhibition. In some severe cases ofanxiety, low doses of benzodiazepines may be necessary until SSRIs become therapeutic. Whenbenzodiazepines are used in this population, benefit may be derived from the cautious dosing ofagents with long half-lives (eg, clonazepam) rather than those with short half-lives (eg, alprazolam).Buspirone (Buspar, Bristol- Myers Squibb) is another reasonable treatment option, especially inpatients with anxiety and aggression. Bryant and colleagues30 suggested that early treatment ofacute stress disorder with cognitive-behavioral therapy might prevent the development of PTSD.Psychotic Symptoms after TBIAlthough the development of chronic psychotic symptoms, such as hallucinations and delusions, is arelatively infrequent result of TBI, these symptoms are not uncommonly observed in the acute phaseafter TBI. When present, these symptoms can be quite debilitating. These post-traumatic psychoticsymptoms are thought to be caused by prefrontal and/or temporal lobe injury.31,32 Although norandomized controlled trials have examined the treatment of secondary psychosis in TBI, treatmentwith atypical antipsychotics, such as risperidone (Risperdal, Janssen), olanzapine (Zyprexa, Lilly),quetiapine (Seroquel, AstraZeneca), and ziprasidone (Geodon, Pfizer), is generally consideredfirst-line.33

It should be noted that clozapine (Clozaril, Novartis) substantially lowers the seizure threshold, whichcan be problematic in brain-injured patients. Clozapine also has anticholinergic properties that canfurther impair cognitive function in this population and may provoke delirium. Treatment with typicalantipsychotic medications that have primarily dopamine2 receptor-blocking properties may cause afunctional decline in patients with TBI who already have diminished dopaminergic circuits as a result

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Neurobehavioral Sequelae of Traumatic Brain InjuryPublished on Psychiatric Times(http://www.psychiatrictimes.com)

of frontal lobe injury. Therefore, atypical antipsychotic agents, which have fewer dopamine-blockingproperties than the typical antipsychotics and greater serotonergic action, are generally preferred.Aggression and Impulsivity after TBIAggression and impulsivity are commonly encountered after brain trauma, especially in the acute/subacute period. Orbitofrontal injury is strongly correlated with impulsive aggression. Severaltreatment strategies have been proposed in patients with TBI. Randomized controlled trials havedemonstrated the effectiveness of b-blockers such as propranolol (Inderal, Wyeth) for themanagement of agitation and aggression in brain-injured patients.34 Valproate has also beenreported to be effective in the treatment of aggression in patients with TBI.35,36 Atypicalantipsychotics, SSRIs, lamotrigine, and buspirone also have been used for managing post-traumaticaggression.37-40

Personality Changes after TBIThe famous case of Phineas Gage illustrates the personality changes commonly observed after TBI,specifically frontal lobe injury. One study found that a personality disorder developed in 23.3% ofpatients as a result of TBI.41 Appropriate treatment of these personality disorders would involve areferral for psychotherapy. Medications such as SSRIs or mood stabilizers can be used to targetspecific symptoms, including aggression and emotional instability.Future Treatment of TBIEarly treatment with neuroprotecting agents may prevent some of the secondary excitotoxic injurythat leads to demise of neurons in the days after the initial brain injury. N-methyl d-aspartic acidreceptor antagonists, such as memantine (Namenda, Forest), may have potential asneuroprotectants, as suggested by experimental studies.42,43 *REFERENCES1. Zhang L, Plotkin RC, Wang G, et al. Cholinergic augmentation with donepezil enhances recovery inshort-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil.2004;85:1050-1055.2. Kaye NS, Townsend JB 3rd, Ivins R. An open-label trial of donepezil (aricept) in the treatment ofpersons with mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2003;15:383-384.3. Masanic CA, Bayley MT, VanReekum R, Simard M. Open-label study of donepezil in traumatic braininjury. Arch Phys Med Rehabil. 2001; 82:896-901.4. Morey CE, Cilo M, Berry J, Cusick C. The effect of Aricept in persons with persistent memorydisorder following traumatic brain injury: a pilot study. Brain Inj. 2003;17:809-815.5. Tenovuo O. Central acetylcholinesterase inhibitors in the treatment of chronic traumatic braininjury--clinical experience in 111 patients. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:61-67.6. Walker W, Seel R, Gibellato M, et al. The effects of Donepezil on traumatic brain injury acuterehabilitation outcomes. Brain Inj. 2004;18:739-750.7. Whelan FJ, Walker MS, Schultz SK. Donepezil in the treatment of cognitive dysfunction associatedwith traumatic brain injury. Ann Clin Psychiatry. 2000;12:131-135.8. Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery intraumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J HeadTrauma Rehabil. 2002;17:300-313.9. Green LB, Hornyak JE, Hurvitz EA. Amantadine in pediatric patients with traumatic brain injury: aretrospective, case-controlled study. Am J Phys Med Rehabil. 2004;83:893-897.10. Kraus MF, Maki P. Effect of amantadine hydrochloride on symptoms of frontal lobe dysfunction inbrain injury: case studies and review. J Neuropsychiatry Clin Neurosci. 1997;9:222-230.11. Van Reekum R, Bayley M, Garner S, et al. N of 1 study: amantadine for the amotivationalsyndrome in a patient with traumatic brain injury. Brain Inj. 1995;9:49-53.12. Whyte J, Hart T, Vaccaro M, et al. Effects of methylphenidate on attention deficits after traumaticbrain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004;83:401-420.13. Mahalick DM, Carmel PW, Greenberg JP, et al. Psychopharmacologic treatment of acquiredattention disorders in children with brain injury. Pediatr Neurosurg. 1998;29:121-126.14. Whyte J, Hart T, Schuster K, et al. Effects of methylphenidate on attentional function aftertraumatic brain injury. A randomized, placebo-controlled trial. Am J Phys Med Rehabil. 1997;76:440-450.15. Plenger PM, Dixon CE, Castillo RM, et al. Subacute methylphenidate treatment for moderate tomoderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. ArchPhys Med Rehabil. 1996;77:536-540.

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Neurobehavioral Sequelae of Traumatic Brain InjuryPublished on Psychiatric Times(http://www.psychiatrictimes.com)

16. Lee H, Kim SW, Kim JM, et al. Comparing effects of methylphenidate, sertraline and placebo onneuropsychiatric sequelae in patients with traumatic brain injury. Hum Psychopharmacol.2005;20:97-104.17. Turner-Stokes L, Hassan N, Pierce K, Clegg F. Managing depression in brain injury rehabilitation:the use of an integrated care pathway and preliminary report of response to sertraline. Clin Rehabil.2002;16:261-268.18. Fann JR, Uomoto JM, Katon WJ. Sertraline in the treatment of major depression following mildtraumatic brain injury. J Neuropsychiatry Clin Neurosci. 2000;12:226-232.19. Marin RS, Fogel BS, Hawkins J, et al. Apathy: a treatable syndrome. J Neuropsychiatry ClinNeurosci. 1995;7:23-30.20. Murai T, Fujimoto S. Rapid cycling bipolar disorder after left temporal polar damage. Brain Inj.2003;17:355-358.21. Jorge RE, Robinson RG, Starkstein SE, et al. Secondary mania following traumatic brain injury. AmJ Psychiatry. 1993;150:916-921.22. Kennedy R, Burnett DM, Greenwald BD. Use of antiepileptics in traumatic brain injury: a reviewfor psychiatrists. Ann Clin Psychiatry. 2001; 13:163-171.23. Kim E, Humaran TJ. Divalproex in the management of neuropsychiatric complications of remoteacquired brain injury. J Neuropsychiatry Clin Neurosci. 2002;14:202-205.24. Monji A, Yoshida I, Koga H, et al. Brain injury-induced rapid-cycling affective disorder successfullytreated with valproate. Psychosomatics. 1999; 40:448-449.25. Yassa R, Cvejic J. Valproate in the treatment of posttraumatic bipolar disorder in apsychogeriatric patient. J Geriatr Psychiatry Neurol. 1994;7:55-57.26. Schneck CD. Bipolar disorder in neurologic illness. Curr Treat Options Neurol. 2002;4:477-486.27. Stewart JT, Hemsath RH. Bipolar illness following traumatic brain injury: treatment with lithiumand carbamazepine. J Clin Psychiatry. 1988; 49:74-75.28. Stengler-Wenzke K, Muller U, Matthes-von-Cramon G. Compulsive-obsessive disorder after severehead trauma: diagnosis and treatment. Psychiatr Prax. 2003;30:37-39.29. Khouzam HR, Donnelly NJ. Remission of traumatic brain injury-induced compulsions duringvenlafaxine treatment. Gen Hosp Psychiatry. 1998; 20:62-63.30. Bryant RA, Moulds M, Guthrie R, Nixon RD. Treating acute stress disorder following mildtraumatic brain injury. Am J Psychiatry. 2003;160: 585-587.31. Zhang Q, Sachdev PS. Psychotic disorder and traumatic brain injury. Curr Psychiatry Rep. 2003;5:197-201.32. Fujii D, Ahmed I. Characteristics of psychotic disorder due to traumatic brain injury: an analysisof case studies in the literature. J Neuropsychiatry Clin Neurosci. 2002;14:130-140.33. McAllister TW, Ferrell RB. Evaluation and treatment of psychosis after traumatic brain injury. NeuroRehabilitation. 2002;17:357-368.34. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation andaggression in people with acquired brain injury. Cochrane Database Syst Rev. 2003;(1):CD003299.35. Lindenmayer JP, Kotsaftis A. Use of sodium valproate in violent and aggressive behaviors: acritical review. J Clin Psychiatry. 2000;61:123-128.36. Wroblewski BA, Joseph AB, Kupfer J, Kalliel K. Effectiveness of valproic acid on destructive andaggressive behaviours in patients with acquired brain injury. Brain Inj. 1997;11:37-47.37. Fava M. Psychopharmacologic treatment of pathologic aggression. Psychiatr Clin North Am.1997;20:427-451.38. Kant R, Smith-Seemiller L, Zeiler D. Treatment of aggression and irritability after head injury. Brain Inj. 1998;12:661-666.39. Pachet A, Friesen S, Winkelaar D, Gray S. Beneficial behavioural effects of lamotrigine intraumatic brain injury. Brain Inj. 2003;17:715-722.40. Ratey JJ, Leveroni CL, Miller AC, et al. Low-dose buspirone to treat agitation and maladaptivebehavior in brain-injured patients: two case reports. J Clin Psychopharmacol. 1992;12:362-364.41. Koponen S, Taiminen T, Portin R, et al. Axis I and II psychiatric disorders after traumatic braininjury: a 30-year follow-up study. Am J Psychiatry. 2002;159:1315-1321.42. Ozsuer H, Gorgulu A, Kiris T, Cobanoglu S. The effects of memantine on lipid peroxidationfollowing closed-head trauma in rats. Neurosurg Rev. 2005;28:143-147.43. Rao VL, Dogan A, Todd KG, et al. Neuroprotection by memantine, a non-competitive NMDAreceptor antagonist after traumatic brain injury in rats. Brain Res. 2001;911:96-100.

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