Postconcussive Syndrome Medication

Patients with head injury may require treatment with psychotropic medication for the specific symptoms of which the patient is suffering. These symptoms include irritability, headaches, insomnia, apathy, and, in rare cases, psychosis.

Brain damage renders patients more sensitive to adverse anticholinergic effects, seizures, and drug-induced parkinsonism. Slower than normal titration may be needed.

Dopamine-blocking agents (eg, haloperidol) and adrenergic-blocking agents (eg, clonidine, prazosin) compromise brain tissue repair in animal laboratory models. Dopamine-potentiating agents (eg, dextroamphetamine) enhance recovery in animal models. These effects have not been documented in humans with head injury, although alpha-blockers, haloperidol, and benzodiazepines may adversely affect functional outcome after strokes.

According to a recent FDA advisory, atypical antipsychotic drugs of various classes (including aripiprazole, risperidone, quetiapine, olanzapine) increase mortality when given for behavioral disorders in patients who are elderly and have dementia. The implication of these findings for the treatment of dementia or behavioral disorders after head injury are unknown. In the studies cited by the FDA, the excess mortality reflected deaths from infections and heart disease, conditions more common in the elderly population than in the younger population of patients with head injury.

Practitioners should be aware, at minimum, that the use of antipsychotic drugs for conditions other than schizophrenia and mania is off-label and should be carefully monitored.

Drug treatments for patients with brain injury are extrapolated from studies of patients after stroke or other types of brain damage. These patients may not be comparable to patients with head injuries, especially those with diffuse axonal injury (DAI). Clinical trials in patients with head injury are typically small. No broad consensus or established guidelines exist regarding psychotropic drug treatment after head injury.

Specific target symptoms and appropriate medications include the following:

• Irritability and chronic aggression - Antiepileptic drugs, SSRIs, olanzapine
• Apathy - Dopamine agonists such as selegiline
• Depression - Selective serotonin reuptake inhibitors (SSRIs), nefazodone, bupropion
• Insomnia - Trazodone, mirtazapine
• Attention, concentration, processing speed - Psychostimulants (improve cognitive processing speed and may improve attention)
• Headaches - Amitriptyline, nonsteroidal anti-inflammatory drugs (NSAIDs), antimigraine drugs
• Anxiety - SSRIs, buspirone

Acute agitation or aggression may be treated with benzodiazepines; however, first-line treatment of chronic symptoms includes drugs having less sedative effects or impact on cognition. Avoid phenobarbital for treating seizures due to sedation. Over-the-counter anticholinergic hypnotics are not to be used for patients with head injury.

Class Summary

Treatment of depressive syndromes due to traumatic brain injury. Indications include signs and symptoms of major depression with or without psychosis, dysthymia, or adjustment disorder.

SSRIs are the antidepressants of choice due to minimal anticholinergic effects. All are equally efficacious. The choice depends on adverse effects and drug interactions. SSRIs also are used to treat behavioral disturbances resulting from head trauma.

Tricyclic antidepressants (TCAs) are used when unable to use SSRIs. Their unfavorable adverse effect profile prompted development of newer antidepressants. Advantages include ability to obtain blood levels, thus ensuring therapeutic response and avoiding toxicity. Prior to initiating, obtain ECG and blood pressure.

Newer antidepressants useful for sleep disturbances include trazodone and mirtazapine. They are structurally unrelated to TCAs, tetracyclics, or MAOIs. Cardiac conduction effects of trazodone are qualitatively dissimilar and quantitatively less pronounced than TCAs and therefore are less toxic in overdose.

Fluoxetine (Prozac)

Selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine.

Citalopram (Celexa)

Enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. No head-to-head comparisons of SSRIs exist, although, based on metabolism and adverse effects, citalopram is considered SSRI of choice for patients with head injury.

Amitriptyline (Elavil)

Tricyclic tertiary amine. Inhibits neuronal reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases concentration in the CNS. Highly anticholinergic, although considered one of the best-studied antidepressants. Use for chronic pain, including headache. Doses for chronic pain are one-half to one-third of those for depression.

Trazodone (Desyrel)

5-HT2–receptor antagonist that inhibits reuptake of 5-HT. Negligible affinity for cholinergic, adrenergic, dopaminergic, or histaminic receptors. Good hypnotic properties. Effective in reducing agitation in patients with head trauma or dementia.

Dextroamphetamine (Dexedrine)

Increases circulating dopamine and norepinephrine in cerebral cortex by blocking reuptake of norepinephrine or dopamine from synapse.

Class Summary

Treatment of hallucinations, ideas of reference, delusional preoccupation, and agitation. Older antipsychotics with strong anticholinergic adverse effects (eg, chlorpromazine, thioridazine) may worsen cognitive function. Potent conventional antipsychotics (eg, haloperidol) have been used in patients with dementia with psychotic symptoms. While these drugs are effective, patients with brain damage are more susceptible to drug-induced parkinsonism. Haloperidol produces high levels of parkinsonian symptoms and risk of irreversible syndrome of tardive dyskinesia.

New antipsychotic drugs (eg, risperidone, olanzapine) may have particular efficacy in treating agitation and psychosis in patients with Alzheimer disease and for cognitive symptoms in schizophrenia. However, these drugs, along with atypical antipsychotic drugs of other classes (eg, aripiprazole, quetiapine) may also increase mortality from infection and heart attacks in older patients with dementia. Taken together, these findings suggest that patients with head injuries may benefit from these drugs, but they should be used with caution and carefully monitored. The adverse effects of somnolence, dizziness, and unsteady gait are of particular concern in patients with head injury. The known potential of many antipsychotic drugs to cause hyperglycemia, weight gain, and type 2 diabetes mellitus is of concern in every patient group.

The atypical antipsychotic drugs olanzapine and ziprasidone are available to be administered parenterally, as may occasionally be needed in an emergency to control agitation or when patients have met local legal standards for the involuntary use of psychotropic medication. Behavioral interventions, such as controlling stimulation or engaging the patient verbally, may allow for the voluntary use of oral medication, which is preferable in all but the most imminently dangerous situations.

Risperidone (Risperdal)

Binds to dopamine D2-receptor with 20 times lower affinity than for 5-HT2-receptor. Improves negative symptoms of psychoses and lowers incidence of extrapyramidal adverse effects.

Quetiapine (Seroquel)

May act by antagonizing dopamine and serotonin effects.

Olanzapine (Zyprexa)

May inhibit serotonin, muscarinic, and dopamine effects.

Class Summary

Behavioral disturbances (eg, chronic aggression, agitation) are severe complications of head injury. Pharmacological agents used to treat these behaviors include antiepileptic drugs, SSRIs, and beta-blockers.

Carbamazepine (Tegretol)

Originally indicated for the treatment of epilepsy involving the temporal lobes. Became known as a mood stabilizer in 1970s when Japanese researchers found it to be helpful in patients with bipolar disease who were refractory to lithium.

Used for reducing frequency and severity of manic and depressive components of bipolar disorder. Not considered first-line treatment. Used to stabilize episodic aggressive behavior.

Double-blind studies have demonstrated moderate effect in decreasing aggressive behavior in patients with dementia and those with impulse control disorders.

Case studies describe effect in patients with seizures or previous head injury. Serum levels of 8-12 mcg/mL may lessen impulsivity, irritability, and hostility in patients with cognitive disorders.

Valproic acid (Depacon, Depakene, Depakote)

Mechanism of action is not established, although activity may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. May potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect. Anticonvulsant used for mood stabilization in patients with head injury. Used in treatment of bipolar disorder. Effective in management of agitation and aggression in patients with dementia. Specific therapeutic range has not been defined for management of aggression. Available in capsules, tablets, syrup, and sprinkles.

Class Summary

The mood stabilizer that is not an anticonvulsant is lithium. Studies have demonstrated potential benefit of lithium for explosive and violent behavior in patients with organic disorders. Double-blind placebo-controlled trials conducted over 16 wk on violent adult prisoners, patients with mental retardation, and patients with brain injury demonstrated decreased impulsivity and aggressive behavior. Lithium levels during the trials were maintained at 0.7-1.0 mEq/L.

Lithium (Eskalith, Lithane, Lithobid, Lithotabs)

Primarily used for acute manic episodes and depression of bipolar disorder and unipolar depression. Also used to treat agitation and violence. Alters sodium transport in nerve and muscle cells, resulting in intraneuronal metabolism of catecholamines; however, specific mechanism of action is unknown.

Class Summary

Used for rapid control of agitation in dementia. They potentially worsen cognition; thus, their use in correcting sleep-wake cycle disturbances or treating anxiety in this population is discouraged. Used primarily to produce rapid calming needed for patients who are violent or agitated.

Lorazepam (Ativan)

DOC for acute agitation in dementia. Short duration and less accumulation with repeated doses.

Class Summary

Effective for treating aggression resulting from head injury. They also are used for reducing restlessness and disinhibition. Treatment for persistent agitation and aggression in organic brain syndromes.

Propranolol (Inderal)

Nonselective beta-adrenergic receptor antagonist. Widely studied for its therapeutic effects on agitation due to organic brain syndrome. Therapeutic effect may be observed within 2-4 wk, improvement within 8 wk.