Traumatic brain injury: Choosing drugs to assist recovery

Table 4

Drugs considered safe and effective
for TBI neurobehavioral symptoms

Target symptom(s)	Drug	Usual daily dosage*
Apathy	Amantadine	100 to 400 mg
	Bromocriptine	1.25 to 100 mg
Cognition	Donepezil
Inattention	Dextroamphetamine	5 to 60 mg
	Methylphenidate	10 to 60 mg
Depression, PTSD symptoms	Fluoxetine	20 to 80 mg
Agitation, mood stabilization	Anticonvulsants
	Lamotrigine	25 to 200 mg
	Divalproex sodium	10 to 15 mg/kg/day†
	Carbamazepine	400 to 1,600 mg‡
	Atypical antipsychotics
	Olanzapine	2.5 to 20 mg
	Quetiapine	50 to 800 mg
	Risperidone	0.5 to 6 mg
	Ziprasidone	20 to 160 mg
	Beta blocker
	Propranolol	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 authors^15,24 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
  

Table 5

Dosing atypical antipsychotics
for agitation and aggression in TBI

Drug	Initial daily dosage*	Maximum daily dosage*
Aripiprazole	2.5 to 5 mg	30 mg
Olanzapine	2.5 mg	20 mg
Quetiapine	12.5 to 50 mg	800 mg
Risperidone	0.25 mg	8 mg
Ziprasidone	20 mg	160 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.

Cognitive impairment. A dozen published studies and case reports indicate that donepezil improves cognition in subacute and chronic TBI. For example:

• An open-label trial showed subjective improvement in cognitive functions in 8 of 10 patients given donepezil.²⁸
  
• In a double-blind, placebo-controlled, crossover trial, short-term memory and attention improved with donepezil in 18 patients with post-acute TBI, as shown by neuropsychological test scores.²⁹
  
• A retrospective case-control study showed no significant difference in cognitive outcome between controls and 18 patients prescribed donepezil but did suggest that cognition improved more rapidly when patients started donepezil earlier in recovery.³⁰
  

Case continued: Back to rehab

We replace Mr. N’s phenytoin with carbamazepine, 700 mg/d (serum level about 12 mcg/mL), discontinue citalopram, and start him on quetiapine as a mood stabilizer, titrating the dosage to 600 mg/d over 3 weeks. We select quetiapine based on experience using it as a mood stabilizer and carbamazepine for additional mood stabilization and seizure prophylaxis.

We continue methadone and oxycodone at the same dosages for pain management, with good results. We eventually switch him from zolpidem to trazodone, 50 mg as needed at bedtime. We discontinue lamotrigine because he is no longer having seizures.

Mr. N tolerates quetiapine and carbamazepine well. The nursing staff reports he is much less irritable and aggressive and his sleep has improved, but he is not oversedated. He returns to and participates in physical, occupational, and speech therapies.

Tips for using medications

Many TBI patients are unusually sensitive to or intolerant of medication side effects. Because no randomized, controlled clinical trials support using any medication in these patients, be cautious. The following recommendations can help:

• Use psychotropics with a low risk of complications.
  
• Start with low dosages and increase gradually to assess side effects and efficacy of medication trials.
  
• Give full trials and adequate dosing before you decide a medication has not improved symptoms sufficiently.
  
• Monitor closely for side effects.
  
• Seek information from family members to evaluate a medication’s effectiveness, as patients’ cognitive deficits may limit their ability to reliably report symptoms.