Drug Therapies for the Neurobehavioral Sequelae of Traumatic Brain Injury
By Shawn J. Kile, MD, James A. Bourgeois, OD, MD, Steven Sugden, MD, Celia H. Chang, MD, Mark E. Servis, MD, and Donald M. Hilty, MD |
March 1, 2007
Dr Kile is chief resident in the department of neurology; Dr Bourgeois is the Alan Stoudemire Professor of Psychosomatic Medicine in the department of psychiatry and behavioral sciences; Dr Sugden is a resident in the department of psychiatry and behavioral sciences; Dr Chang is assistant professor in the department of neurology; and Drs Servis and Hilty are associate professors in the department of psychiatry and behavioral sciences at the UC Davis Medical Center, University of California, Davis. The authors report that they have no conflicts of interest regarding the subject matter of this article.
Affective symptoms after TBI
Depression. Depression is probably the most commonly encountered disorder after TBI and is most likely caused by disruption of multiple neurotransmitter homeostasis. SSRIs—specifically sertraline—have been studied for the treatment of depression after TBI and have been found to be effective.16-18
Although there is a lack of studies specifically investigating treatment of depression after TBI with this class of medications, the dual serotonergic and noradrenergic agents venlafaxine and duloxetine(Drug information on duloxetine) are reasonable alternative choices.
Bupropion is another treatment option, especially in a patient with depression who has significant anergia or apathy.19 Because of the anticholinergic effects that further impair cognitive function and increase the risk of delirium, tricyclic antidepressants should be avoided in those patients with TBI in whom cognitive dysfunction or delirium is a concern.
Bipolar symptoms. Variants of pure unipolar mania, as well as the opposite extreme of rapid cycling-type bipolar symptoms, can be observed in patients with TBI. Some reports suggest that these novel bipolar symptoms may correlate with temporal polar injury.20,21 Treatment with mood-stabilizing antiepileptic drugs has been shown to be effective in such patients.22
Of the antiepileptics, valproate and divalproex sodium(Drug information on divalproex sodium) have been studied the most and are reported to be effective in treating posttraumatic bipolar symptoms.23-25 Carbamazepine(Drug information on carbamazepine) has also been reported to be effective in treating bipolar symptoms in patients with TBI.26,27
Although not specifically investigated for use in patients with TBI who have bipolar symptoms, lamotrigine(Drug information on lamotrigine) is another reasonable treatment option that has been used for managing behavioral symptoms in TBI. Atypical antipsychotics may be another treatment option, especially in patients who have bipolar disorder accompanied by psychotic features.
Lithium carbonate should be avoided in patients with TBI. It lowers the seizure threshold, has the potential for neurotoxicity, and has a low therapeutic index. Furthermore, the monitoring required in cognitively impaired patients contributes to nonadherence.
Anxiety symptoms after TBI
Anxiety syndromes, specifically acute stress disorder, posttraumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder, have been reported after TBI. 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 psychopharmacological agents for the treatment of anxiety disorders in patients with TBI; however, case reports support the use of SSRIs and venlafaxine.28,29
Benzodiazepines should generally be avoided in patients with TBI because of the potential for further cognitive dysfunction, as well as behavioral disinhibition. In some severe cases of anxiety, low doses of benzodiazepines may be necessary until SSRIs become therapeutic. When benzodiazepines are used in this population, benefit may be derived from the cautious dosing of agents with long half-lives (eg, clonazepam(Drug information on clonazepam)) rather than those with short half-lives (eg, alprazolam(Drug information on alprazolam)).
Buspirone is another reasonable treatment option, especially in patients with anxiety and aggression. Bryant and colleagues30 suggested that early treatment of acute stress disorder with cognitive-behavioral therapy might also prevent the development of PTSD.
Psychotic symptoms after TBI
Although the development of chronic psychotic symptoms, such as hallucinations and delusions, is a relatively infrequent result of TBI, these symptoms are not uncommonly observed in the acute phase after TBI. When present, these symptoms can be quite debilitating.
Prefrontal and/or temporal lobe injury is thought to cause these posttraumatic psychotic symptoms.31,32 Although no randomized controlled trials have examined the treatment of secondary psychosis in TBI, treatment with atypical antipsychotics, such as risperidone(Drug information on risperidone), olanzapine(Drug information on olanzapine), quetiapine(Drug information on quetiapine), and ziprasidone(Drug information on ziprasidone), is generally considered first-line.33
It should be noted that clozapine(Drug information on clozapine) substantially lowers the seizure threshold, which can be problematic in brain- injured patients. Clozapine also has anticholinergic properties that can further impair cognitive function in this population and may provoke delirium.
Treatment with typical antipsychotic medications that have primarily dopamine(Drug information on dopamine)2 receptor-blocking properties may cause a functional decline in patients with TBI who already have diminished dopaminergic circuits as a result of frontal lobe injury. Therefore, atypical antipsychotic agents—which have fewer dopamine-blocking properties than the typical antipsychotics and greater serotonergic action—are generally preferred.
Aggression and impulsivity after TBI
Aggression and impulsivity are commonly encountered after brain trauma, especially in the acute/subacute period. Orbitofrontal injury is strongly correlated with impulsive aggression. Several treatment strategies have been proposed. Randomized controlled trials have demonstrated the effectiveness of ß-blockers such as propranolol(Drug information on propranolol) for the management of agitation and aggression in brain-injured patients.34 Valproate(Drug information on valproate) has also been reported to be effective in the treatment of aggression in patients with TBI.35,36 Atypical antipsychotics, SSRIs, lamotrigine, and buspirone(Drug information on buspirone) also have been used for managing posttraumatic aggression.37-40
Personality changes after TBI
The 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% of patients as a result of TBI.41 Appropriate treatment of these personality disorders would involve a referral for psychotherapy. Medications such as SSRIs or mood stabilizers can be used to target specific symptoms, including aggression and emotional instability.
Future treatment of TBI
Early treatment with neuroprotecting agents may prevent some of the secondary excitotoxic injuries that lead to the demise of neurons in the days after the initial brain injury. N-methyl-d- aspartic acid receptor antagonists, such as memantine(Drug information on memantine), may have potential as neuroprotectants, as suggested by experimental studies.42,43
This article first appeared in Applied Neurology.
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