Rational Neuropharmacology in Traumatic Brain Injury

Durga Roy and Vani Rao

BACKGROUND

Neuropsychiatric impairments are common after traumatic brain injury (TBI). These include cognitive impairment, mood and anxiety disorders, psychosis, behavioral problems, apathy, and sleep disturbance. Table 37.1 highlights the prevalence, core features, and first-line treatment of post-TBI neuropsychiatric symptoms and syndromes [1,2]. It is important to remember that most medications used for TBI neuropsychiatric sequelae are off-label. The field is in need of well-designed treatment studies. More detailed descriptions of various disorders and their management, including less commonly used medications not mentioned in this chapter, can be found elsewhere (see Additional Reading). This chapter will provide a brief overview of the pharmacological treatment of common neuropsychiatric sequelae of TBI.

TABLE 37.1 Prevalence, Core Features, and First-Line Treatment of Post-TBI Neuropsychiatric Syndromes

GENERAL GUIDELINES FOR MANAGEMENT

Choose a Medication

In general, pharmacotherapy for post-TBI disorders is similar to that for primary psychiatric disorders. There are few well-designed, randomized, placebo controlled trials to guide treatment decisions in this population. Evidence is limited and consists of few clinical trials, case reports, and case series.

Start Low and Go Slow

A typical starting point would be one-third to one-half the usually recommended dose. Increase the dose slowly. TBI patients are very sensitive to side effects of medications. Medications with known adverse central nervous system (CNS) effects, such as sedatives or anticholinergic drugs, should be avoided whenever possible as they have the potential to impair cognition and impede neural plasticity.

Minimize the Number of Medications

Treat at an adequate dose and for an appropriate length of time with a single agent before switching medications. If there is a partial response, consider augmenting with another agent. Because CNS side effects are additive, use caution when prescribing more than one psychotropic agent. Watch for drug–drug interactions and monitor serum levels of medications if available.

Consider Coexisting Medical Problems

As seizure disorders are more common in TBI patients than in the general population, drugs that lower the seizure threshold—for example, bupropion, clozapine, and clomipramine—should be used with caution.

Caution

Avoid anticonvulsants such as phenytoin, benzodiazepines, and first-generation antipsychotics such as haloperidol in the acute post-TBI period as there is strong evidence that they can worsen cognitive functioning [8] and adversely impact neural plasticity [9]. Anticholinergics (e.g., hydroxyzine) and antihistamines (e.g., diphenhydramine) should also be avoided due to their adverse effects on the CNS. Monoamine oxidase inhibitors should be avoided due to their extensive food and drug interactions.

TREATMENT OF SPECIFIC POST-TBI DISORDERS

Cognitive Impairment

A. Arousal: Psychostimulants and dopaminergic agonists have been used in the treatment of decreased arousal after TBI. Amantadine has been shown to increase arousal post injury in a review, several case reports, retrospective studies, and randomized controlled trials with initiation from 3 days to 5 months post injury [10–12]. Methylphenidate has also been shown to improve decreased arousal during rehabilitation following TBI [13,14].

B. Memory impairment: Cholinergic augmentation with cholinesterase inhibitors is a reasonable first-line treatment for memory impairment. Donepezil has been studied for impairments in both memory and attention in moderate to severe TBI. Though the evidence is not robust, donepezil has been found to improve memory, IQ, as well as attention, which has been the rationale for its common use in TBI-related memory impairment [15]. Rivastigmine has been demonstrated to be safe, well tolerated, and effective in patients with moderate to severe TBI [16].

C. Impaired attention and slow processing speed: Psychostimulants are the mainstay of treatment for impaired attention and processing speed. Commonly used psychostimulants include methylphenidate, amphetamine, dextroamphetamine, and amphetamine sulfate. Often, symptoms consistent with dysexecutive syndrome including deficits in attention, focus, and goal-directed thinking are targets of these agents. Methylphenidate has been studied extensively in moderate to severe TBI [17] and has been shown to have positive effects on attention, sustained attention, vigilance, and processing speed. The effects on memory and distractibility are more unclear. Dextroamphetamine has been shown to improve measures of verbal learning, cognitive speed, sustained attention, reaction time, and behavioral ratings [18]. Low-dose milnacipran, a serotonin-norepinephrine reuptake inhibitor, might also improve inattention. In one recent clinical trial involving 18 patients, it was shown to improve measures of attention and information processing in nondepressed individuals with brain injury and to improve scores on several subscales of cognitive dysfunction in neuropsychological testing [19]. If this finding can be replicated in larger trials with milnacipran and/or the newer agent levomilnacipran, these agents may be novel new options for treatment of impaired attention in TBI patients.

D. Executive dysfunction: Bromocriptine and amantadine [20] can be used to treat executive dysfunction. Amantadine has unique properties. It serves as both a dopaminergic agent (increases release and blocks reuptake of dopamine) and is also a weak antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. In addition, it also possesses noradrenergic properties, and therefore has the potential to influence multiple cognitive domains simultaneously (arousal, attention, processing speed). These agents also have beneficial effects on attention and general cognitive functioning. Noradrenergic agonist agents such as atomoxetine, which increase norepinephrine (and to a lesser extent, dopamine) availability, can also be considered for treatment of attention deficits. These agents may also enhance learning and memory.

Depression (see also Chapter 53)

A. Selective serotonin reuptake inhibitors (SSRIs): SSRIs are the first-line treatment for post-TBI depression because of their safety and tolerability as compared with tricyclic antidepressants. Sertraline, the most dopaminergic of the SSRIs, has the best evidence supporting its use [7] and is the authors’ preferred SSRI. Other commonly used SSRIs include citalopram and escitalopram. Citalopram has been studied extensively and been shown to increase rates of remission from episodes of major depression in open label studies [21,22]. The use of SSRIs such as fluoxetine and paroxetine have a higher potential for drug–drug interactions due to inhibition of various enzymes in the cytochrome P450 system [23].

B. Serotonin/norepinephrine reuptake inhibitors (SNRIs): SNRIs, dual reuptake inhibitors of both serotonin and norepinephrine (e.g., venlafaxine, duloxetine), may also be effective. SNRIs can be considered as first-line agents in persons with depression and chronic pain.

C. Tricyclic antidepressants (TCAs): TCAs, which block reuptake of norepinephrine and serotonin, can be quite effective for depression in some TBI patients. Although amitriptyline is recommended by certain groups [7], the authors prefer nortriptyline and desipramine because they are the least anticholinergic. Desipramine has been shown to be effective in treating patients with depression who suffered severe TBI [24]. Due to their unfavorable side effect profile, most clinicians use TCAs only if an initial trial of SSRIs has been unsuccessful.

D. Mirtazapine: Mirtazapine, a presynaptic alpha-2 adrenergic and serotonin receptor antagonist, can be especially useful when insomnia and/or anorexia are presenting comorbid symptoms.

E. Dopamine-Norepinephrine Reuptake Inhibitors (DNRI): Bupropion, which facilitates dopamine transmission and has effects on norepinephrine, is known to lower the seizure threshold. When it must be used, the long-acting XL form is preferred with a daily dosage not to exceed 300 mg.

F. Neuroleptics: In cases of major depression with psychotic features, or in cases of depression with severe agitation or aggression, atypical antipsychotics (also called second generation antipsychotics; e.g., risperidone, olanzapine) at standard doses may be used in conjunction with antidepressants. First-generation antipsychotics such as haloperidol should be avoided as animal studies reveal that they can increase neuronal toxicity [25] and impede neural plasticity [9]. Further, dopamine blockade is relatively contraindicated after TBI, because these patients are typically dopamine-deficient.

G. Psychostimulants: Methylphenidate might also have antidepressant effects comparable to those observed with sertraline [26].

Mania

A. Anticonvulsants: Anticonvulsants such as valproate [27] are the first-line treatment for post-TBI mania and bipolar disorder. Close monitoring of serum levels, liver function, and blood counts is recommended. Carbamezepine has also been studied in individual cases and shown to be effective in treating symptoms of post-TBI mania [28].

B. Lithium: Anecdotal reports [29] and animal studies [30] suggest efficacy but clinical trials are needed. As TBI patients are particularly prone to its neurotoxic side effects, lithium should be used with caution and is usually reserved for patients with a prior history of mania. Serum levels of lithium and kidney and thyroid functions should be regularly monitored.

C. Neuroleptics: Atypical antipsychotics (e.g., risperidone and olanzapine) may be preferred when psychosis, agitation, and/or restlessness are present.

Anxiety

A. SSRIs: Treatment of persistent anxiety often includes the use of SSRIs, for example, sertraline, at doses that are similar to or sometimes higher than those used for major depression.

B. SNRIs: SNRIs may also be a good option for anxiety in TBI patients.

C. Buspirone: Buspirone, a serotonergic and weakly dopaminergic agent, can be used safely as an anxiolytic in patients with TBI. Although it has a slower onset of action than benzodiazepines, buspirone can be considered as a first-line agent because of its benign side-effect profile and lack of significant drug–drug interactions.

D. Other agents: While benzodiazepines have been commonly prescribed agents for idiopathic anxiety and often seen used as anxiolytics in the non-TBI population, they are generally avoided in the treatment of anxiety in patients with TBI as they have been shown to impair neuronal growth. In addition, benzodiazepines may increase the risk of falls and may induce a paradoxical disinhibition in patients with TBI [31].

E. Newer antidepressants: The newer antidepressants vilazodone, levomilnacipran, and vorioxetine may show promise in post-TBI depression; however, these drugs have not been studied in the TBI population [32].

Psychosis

A. Neuroleptics: Atypical antipsychotics are the drugs of choice for psychosis following TBI. They are preferred over the older “typical” antipsychotics because of their lower incidences of neurological side effects such as extrapyramidal side effects (EPS) and because they do not inhibit dopamine release to the same degrees. Risperidone is a good first-line agent and the one that the authors prefer because of its favorable risk-to-benefit ratio. Olanzapine is recommended by the Neurobehavioral Guidelines Working Group [7] on the basis of case reports supporting its effectiveness [33,34]; however, metabolic side effects such as weight gain may limit its long-term use. Other atypical antipsychotics may also be reasonable options [35].

Caution: Clozapine should be avoided because of its potential to induce seizures and its anticholingeric effects. It should also be noted that clozapine use requires monitoring for neutropenia via the absolute neutrophil count (ANC). Treatment with clozapine should be interrupted if neutropenia (ANC less than 1000 cells per microliter) is suspected to be clozapine-induced [36].

B. Anticonvulsants: If there is no improvement on neuroleptics, anticonvulsants can be tried. Anticonvulsants can be useful for associated agitation.

Behavioral Dyscontrol

A syndrome of behavioral dyscontrol characterized by mood lability, agitation, aggression, impulsivity, disinhibition, and/or apathy can often be seen in TBI. Patients can often act impulsively in response to certain stimuli. For the treatment of behavior dyscontrol, it is important to determine if the behavioral symptoms are secondary to an affective disorder, psychosis, or cognitive deficits and then choose medications accordingly [37].

A. Antidepressants: In general, the authors tend to use low-dose SSRIs as a first-line treatment for chronic agitation and aggression, especially if comorbid depressive symptoms exist. Antidepressants have also been shown to be effective in cases of affective lability and syndromes of impulsivity and/or disinhibition related to TBI, such as pathological laughter and crying (formerly referred to as pseudobulbar affect or emotional incontinence). Dextromethorphan/quinine combination has not been studied in TBI; however, it has been FDA approved for use in pseudobulbar affect, specifically in the syndromes of amyotrophic lateral sclerosis and multiple sclerosis. It’s potential value in TBI related behavioral dyscontrol warrants clinical investigation [38].

B. Mood stabilizers: Mood stabilizers such as anticonvulsants are routinely used in the treatment of post-TBI lability, impulsivity, and/or disinhibition.

C. Beta blockers: Small randomized controlled trials have demonstrated the efficacy of beta-adrenergic receptor blocker agents for the treatment of post-TBI aggression [39], and guidelines have been established for their use [7]. Beta-blockers selective for the beta-1 subtype (e.g., metoprolol) are generally preferred because they tend to result in less CNS depression.

D. Neuroleptics: Acutely, if the patient is getting increasingly agitated, low-dose atypical antipsychotics can be used. Note, however, that antipsychotic medications do not help with chronic nonpsychotic aggression.

E. Psychostimulants: Stimulants may be useful for impulsivity and disinhibition, especially if the symptoms are part of a dysexecutive syndrome.

F. Other agents: Gabapentin has also recently been studied in postconcussive syndrome and has shown some efficacy in addressing mood lability, irritability, and anxiety in addition to headaches, pain, and sleep disturbances [40].

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