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Drug Therapies for the Neurobehavioral Sequelae of Traumatic Brain Injury

Drug Therapies for the Neurobehavioral Sequelae of Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality, especially in young adults. Recognition and early accurate diagnosis of neurobehavioral TBI sequelae are important in reducing the severity of postinjury symptoms. Sequelae of TBI include cognitive impairments, personality changes, aggression, impulsivity, apathy, anxiety, depression, mania, and psychosis.

Patients often present with nonspecific complaints of headache or dizziness after a head injury. Additional history taking and comprehensive mental status testing frequently reveal symptoms of depression or memory dysfunction, and psychiatric consultation may be sought. Because the neuropathology of TBI is diffuse and affects many areas of the brain, a multiplicity of neurobehavioral symptoms is common after TBI. This makes study of the post-TBI population challenging and may be the reason for the relatively few studies about treating neurobehavioral symptoms after TBI.

Although the following classification breaks down the manifestations of TBI according to psychiatric symptom dimensions that have an intuitive correlation with specific psychiatric interventions, a typical patient may require intervention with multiple medications to treat symptoms in various dimensions. On the other hand, after reviewing the following reasonable treatment options, a knowledgeable physician may choose a medication that targets multiple neurobehavioral sequelae of TBI (Table). However, medical management represents only one facet of the treatment of TBI; optimal treatment often will also require cognitive rehabilitation, behavioral training, counseling, and other individualized therapeutic modalities.

Treatments recommended for
patients with psychiatric symptoms
following traumatic brain injury
  Symptoms   Medication  
Impaired memory  
Acetylcholinesterase inhibitor
Decreased arousal, apathy, amotivation  
Impaired processing/distractibility  
Depression with anergia/apathy  
Mania/hypomania (bipolar)  
Valproate, carbamazepine, lamotrigine;
avoid lithium
Bipolar disorder with psychosis and aggression  
Atypical antipsychotic
SSRI, SNRI, benzodiazepine
Anxiety with aggression  
Buspirone, SSRI
Anxiety with depression  
Atypical antipsychotic; avoid clozapine
ß-Blocker, valproate, carbamazepine,
lamotrigine, atypical antipsychotic, SSRI,
SNRI, serotonin-norepinephrine reuptake inhibitor.  

Cognitive dysfunction after TBI
Memory impairment. Memory impairment is a common problem after TBI. The sensitivity of the hippocampus to physiological stress and the mesial temporal predisposition to injury caused by the sphenoidal bony protuberances probably play a role.

Acetylcholinesterase inhibitors have demonstrated promising results in the treatment of memory dysfunction after TBI. Donepezil has been the most studied acetylcholinesterase inhibitor. Zhang and colleagues1 conducted a prospective, randomized controlled study of donepezil in brain-injured patients in which significant improvements were achieved during the treatment phases on both memory and concentration measures. Several other nonrandomized studies have evaluated cognitive im-pairment secondary to TBI and the open-label use of donepezil.2-7 These studies also support the finding that donepezil improves overall memory and attention.

Diminished alertness, apathy, and lack of motivation. Diminished alertness, apathy, and lack of motivation are common symptoms after TBI, particularly after diffuse axonal injury and bifrontal lobe injury. Patients often will not seek treatment themselves; family members usually bring them in for evaluation because of a decline in function. Patients may even present as abulic.

Amantadine is a dopaminergic medication that has been studied as a treatment for patients with TBI. It was initially proposed as a treatment because the frontal lobes are rich in dopaminergic neurons. Therefore, maximizing dopamine function in patients with bifrontal injury may result in improved function.

A prospective, randomized controlled study, conducted by Meythaler and colleagues,8 investigated the use of amantadine in patients with TBI and concluded that amantadine therapy was associated with a consistent trend toward improved neurorecovery with functional outcome measures. Other studies have demonstrated that amantadine specifically improved alertness, initiation, and motivation in patients with TBI.9-11

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


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