Traumatic brain injury: Choosing drugs to assist recovery
Some agents can worsen neurobehavioral symptoms.
Choosing medications for patients with traumatic brain injury (TBI) requires caution; some drugs slow their recovery, and no standard post-TBI treatment exists.
As consulting psychiatrist on a TBI rehabilitation team, I am asked to manage enduring cognitive and emotional problems—aggression, apathy, learning disabilities, dementia—in patients with moderate to severe head injuries. This article describes how we apply available evidence to treat neurobehavioral symptoms in these patients.
Case: An iraq war casualty
The physical medicine and rehabilitation service asks for help in managing agitation, anxiety, and nightmares in Mr. N, age 20, a U.S. combat soldier. While on patrol 2 months ago in Iraq, he suffered a penetrating right frontoparietal brain injury from an improvised explosive device.
Mr. N has undergone a right temporoparietal craniectomy with debridement, ventriculostomy placement, and scalp flap closure. He has had seizures and then pancreatitis—thought to be caused by divalproex prescribed to treat the seizures. Divalproex was replaced with phenytoin at our hospital, and the pancreatitis resolved.
How serious an injury?
TBI ranges from self-limited concussion to devastating, permanent CNS impairment and life-long disability. Brain injuries from sudden impact—from assaults, falls, motor vehicle accidents, combat, or sports—can cause diffuse axonal injury and confusion or unconsciousness, even without radiographic evidence of cerebral bleeding, edema, or mass effect.
No hierarchy or nomenclature is universally accepted for TBI. The term “concussion” is generally used for milder injury and TBI for more-severe injuries.
Concussion. The American Academy of Neurology defines concussion as a trauma-induced alteration in mental status that may or may not involve loss of consciousness. Confusion and amnesia—the hallmarks of concussion—may occur immediately after the head trauma or several minutes later.1 This definition recognizes three concussion grades:
- Grade 1: confusion lasts <15 minutes, with no loss of consciousness (LOC)
- Grade 2: confusion persists >15 minutes but without LOC
- Grade 3: concussion with LOC. The confusional state is marked by disorientation, delayed verbal and motor responses, inattention, incoordination, emotional lability, and slurred or incoherent speech.
TBI. The severity of an injury with LOC is usually determined by four factors: the patient’s initial Glasgow Coma Scale (GCS) score in the emergency department (Table 1),2 neuroimaging, duration of coma, and duration of posttraumatic amnesia (PTA).
- Mild TBI: GCS 13 to 15, LOC <20 to 30 minutes, PTA <24 hours, and normal neuroimaging studies.1,3
- Moderate TBI: GCS 9 to 12, LOC 30 minutes to 7 days, and PTA 24 hours to 7 days.
- Severe TBI: GCS ≤8, LOC, and PTA >7 days,4 or any focal neuroimaging abnormalities.3
Using Glasgow Coma Scale scores to evaluate brain injury severity
Best eye response
No eye opening
Eye opening to pain
Eye opening to verbal command
Eyes open spontaneously
Best verbal response
No verbal response
Best motor response
No motor response
Extension to pain
Flexion to pain
Withdrawal from pain
GCS total score ≥12 is mild injury, 9 to 11 is moderate, and ≤8 is severe (90% of patients with scores ≤8 are in a coma). Coma is defined as not opening eyes, not obeying commands, and not saying understandable words. Composite scores with eye, verbal, and motor responses (such as E3V3M5) are clinically more useful than totals.
Source: Reference 2.
Case continued: ‘They’re hurting me’
Mr. N meets criteria for severe TBI. He is periodically agitated and aggressive and refuses to return to physical therapy, complaining that rehabilitation nurses are intentionally hurting him. He occasionally hits the staff and throws things. His medications include:
- phenytoin, 100 mg every 6 hours for seizure prophylaxis
- lamotrigine, 50 mg bid for seizure prophylaxis
- zolpidem, 5 mg as needed at bedtime for pain
- methadone, 10 mg/d for pain
- oxycodone, 5 mg every 4 hours as needed for breakthrough pain.
Mr. N’s recovery 2 months after injury is rated as Rancho level IV, indicating that he remains confused and agitated. He requires maximal assistance with bed mobility and transfers, upper and lower extremity dressing, and rolling his wheelchair with both feet. He is incontinent of bowel and bladder.
For patients such as Mr. N, TBI recovery progress is measured with the Rancho Los Amigos Scale.
The original Rancho scale—developed in 1972 by staff at the Rancho Los Amigos rehabilitation hospital in Downey, CA—described eight levels of cognitive and adaptive functioning, from coma and total care through normal cognition and independence. A 1997 revised version separates the highest cognitive functioning level (VIII, purposeful, appropriate function) into three parts, expanding the scale to 10 levels (Table 2).5
Of course, not all TBI patients begin recovery at Rancho level I, and unfortunately not all achieve level X. Some experience dementia caused by head trauma, with persistent memory impairment and cognitive deficits in language, apraxia, agnosia, or executive function.6
Most patients recover as predicted by the initial injury’s severity. Others experience diffuse cerebral swelling with sudden, rapid deterioration after what appeared to be a grade 1 or grade 2 concussion. Diffuse cerebral swelling is sometimes considered a “second-impact syndrome,” but it can also occur after a single impact.7 A second TBI is not universally believed to cause the precipitous decline, but animal studies suggest an additive effect of rapid sequential TBI.8
10-level Rancho Los Amigos Scale for assessing TBI recovery
Cognitive and adaptive function
Confused, inappropriate non-agitated
Stand-by assistanceon request
Source: Traumatic Brain Injury Resource Guide. www.neuroskills.com.
Post-TBI syndromes. Concussion and TBI share diffuse axonal injury as a putative pathophysiologic mechanism. Post-concussion and post-TBI syndromes are similar but vary in severity and duration. Signs and symptoms include headache, light-headedness or dizziness, poor attention and concentration, irritability with low frustration tolerance, anxiety or depression, sensitivity to bright light or loud noise, and sleep disturbance.1
Recovery for a patient such as Mr. N with Rancho level IV to V TBI may be complicated by marked mood lability, spontaneous aggression, psychomotor agitation, extremely short attention with marked distractibility, little to no short-term memory, and noncooperation with treatment and care. Patients may also show disorders of diminished motivation, characterized by normal consciousness but decreased goal-directed behavior and affective flattening.9
Case continued: Calling in reinforcements
Besides combat nightmares, Mr. N is experiencing other signs of posttraumatic stress disorder (PTSD): intrusive memories of dead comrades, anhedonia, insomnia, irritability, and hypervigilance. We recommend a trial of citalopram, 10 mg/d, but within 1 week he becomes more irritable, agitated, and aggressive, with worsening sleep. We arrange a meeting to obtain collateral information from Mr. N’s aunt, mother, and clinical psychologist. We learn that a first-degree relative had bipolar disorder, and Mr. N lived with various relatives during childhood.
As a child, Mr. N was easily angered, hyperactive, unpredictably aggressive with peers, and impulsive. He was diagnosed with “explosive disorder” at age 8. A psychiatrist prescribed methylphenidate (which helped) and paroxetine (which worsened his behavior and aggression). Based on this history, we make a presumptive diagnosis of comorbid bipolar disorder.
Comorbidities. Adolescents and adults with pre-existing attention-deficit/hyperactivity disorder or bipolar disorder may be predisposed to carelessness or risk taking that lead to accidents and TBI. Likewise, alcoholism and substance use disorders are risk factors for head injuries. These pre-existing conditions will complicate the post-TBI course and must be treated concurrently.
Depression and PTSD may follow a head injury and complicate recovery. In fact, post-TBI symptoms—poor sleep, poor memory and concentration, and irritability—are common to both depression and PTSD.
A team approach. Regardless of its severity or recovery stage, TBI requires multidisciplinary treatment. Physical, occupational, and speech therapies are essential initially. As recovery progresses, vocational rehabilitation may need to be added. Throughout rehabilitation, supportive individual and family therapy can help patients reintegrate into the community. Psychologists, neuropsychologists, and clinical social workers are indispensable to the treatment team.
Using medications to manage post-TBI syndromes is difficult and controversial. No standard regimen exists, and few clinical trials guide treatment. Small, uncontrolled studies (human and animal) suggest commonly prescribed drugs may worsen outcomes (Table 3).10,11 For example:
- Cognitive function improved in three TBI patients after thioridazine was discontinued in two and haloperidol in one.12
- Haloperidol given to 11 patients with TBI made no difference in rehabilitation outcomes when compared with 15 patients who did not receive the antipsychotic. Those receiving haloperidol also had longer post-trauma amnesia (5 to 30 weeks), compared with the untreated group (1 to 18 weeks).13
- In animal studies of TBI, motor recovery was slowed with haloperidol but not olanzapine,14,15 and with clonidine,16 phenytoin,17 and trazodone.18 Phenobarbitol.19 and diazepam20 have been associated with delayed behavioral recovery and chronic behavior problems, respectively, in rats with TBI. How these agents might affect human patients is speculative.
Medications with potential to impede TBI recovery*
*Suggested by animal or clinical studies
Source: References 11-20
Apathy and inattention. A review of 63 papers found no strong evidence that drugs are effective for TBI’s neurobehavioral disorders, although weak evidence shows that some drug classes can reduce target symptoms—such as psychostimulants for apathy, inattention, and slowness (Table 4).21 Other reports suggest reasonable approaches:
- Psychostimulants have improved recovery of motor function in animal trials if given before physical therapy.14
- Stimulants and dopaminergic agonists such as bromocriptine and amantadine might help disorders of diminished motivation.22
- Dextroamphetamine and methylphenidate have improved impulsivity, memory, and concentration in a patient with TBI.23
Drugs considered safe and effective
for TBI neurobehavioral symptoms
Usual daily dosage*
100 to 400 mg
1.25 to 100 mg
5 to 60 mg
10 to 60 mg
Depression, PTSD symptoms
20 to 80 mg
Agitation, mood stabilization
25 to 200 mg
10 to 15 mg/kg/day†
400 to 1,600 mg‡
2.5 to 20 mg
50 to 800 mg
0.5 to 6 mg
20 to 160 mg
20 to 480 mg
PTSD: posttraumatic stress disorder
* Dosage may be divided; see full prescribing information.
† Adjust dosage to achieve serum level of 50 to 100 mcg/mL.
‡ Adjust dosage to achieve serum level of 4 to 12 mcg/mL.
Agitation and aggression in TBI are more difficult to treat than apathy or inattention. Some authors15,24 suggest that atypical antipsychotics are more effective than neuroleptics for these symptoms and less likely to cause adverse effects (Table 5).
Small studies of anticonvulsants for post-TBI agitation report:
- valproic acid might improve behavioral control and decrease aggression, and it did not worsen performance on neuropsychological testing
- carbamazepine reduced agitation in seven TBI patients and reduced anger outbursts in 8 of 10 others
- gabapentin caused paradoxical effects in two TBI patients25
- lamotrigine improved agitation in one TBI patient.26
Five studies show preliminary evidence that beta blockers (usually propranolol) can reduce assaultive behavior and temper outbursts in TBI patients. Relatively high dosages are usually needed, such as:
- propranolol, 420 to 520 mg/d
- pindolol, 60 mg/d
- metoprolol, 200 mg/d.21
Dosing atypical antipsychotics
for agitation and aggression in TBI
Initial daily dosage*
Maximum daily dosage*
2.5 to 5 mg
12.5 to 50 mg
*Daily dosages may be divided
Psychiatric comorbidity. In TBI patients with comorbid bipolar disorder, mood stabilization with an atypical antipsychotic, anticonvulsant (divalproex sodium, carbamazepine), or a combination of the two is first-line therapy. No evidence suggests that using lithium in the absence of mania improves aggression, agitation, or other neurobehavioral symptoms in TBI patients.21
Depression and PTSD in TBI patients are considered indications for selective serotonin reuptake inhibitors (SSRIs). Animal data suggest that fluoxetine is safe for patients with TBI,27 though no human data have been published.
For PTSD with bipolar depression, we usually prescribe lamotrigine or combine an atypical antipsychotic with an SSRI. Lithium would be second-line therapy. PTSD with bipolar mania is more difficult to treat because little evidence guides medication choices. As with depression and PTSD, we usually combine an atypical antipsychotic with an SSRI. We try to control manic and psychotic symptoms first, then add the SSRI for anxiety after the mood becomes more stable.