Pharmacological Management of the Psychiatric Aspects of Traumatic Brain Injury

April 24, 2019

Traumatic brain injury (TBI) is a public health epidemic. Psychiatric symptoms after TBI are not just common, but also troublesome.

Traumatic brain injury (TBI) is a public health epidemic. Approximately 2.8 million people sustain a TBI annually; of these, approximately 50,000 die, 282,000 are hospitalized, and 2.5 million are discharged from an emergency department.1 Mild TBI or concussion accounts for the majority of TBIs. Falls are the most common cause of TBI, followed by assault and motor vehicle accidents. According to recent statistics, during a 6-year period from 2007 to 2013, rates of TBI-related ER visits increased by 47%, but rates of hospitalization and death decreased by 2.5% and 5% respectively, underscoring the importance of managing TBI morbidity.1

Psychiatric disturbances are the most common long-term sequelae of TBI. In a recent article on the epidemiology and natural history of psychiatric disorders after TBI, Ponsford and colleagues2 noted that compared with the general population, patients with TBI have increased incidence of depressive disorder, anxiety disorder, and PTSD; depressive disorders are likely to be chronic and persistent.

In this article, we define TBI psychiatric disturbances as the development of psychiatric symptoms (emotional, behavioral, or cognitive) after the occurrence of a single or multiple TBIs. It may not always be possible to establish a causative link between TBI and the onset of psychiatric problems. When not possible, TBI should be considered as a treatment-informing medical comorbidity rather than an etiological factor.

Appropriate management of psychiatric disturbances can result in better outcomes, improved quality of life, and decreased societal impact. Management of TBI psychiatric disturbances should always be multidisciplinary and include both pharmacological and non-pharmacological interventions. An extensive armamentarium of pharmacological options is available, and there have been a number of randomized controlled trials and meta-analyses (Table).

Emotional problems

TBI-associated depression. TBI-associated depression is characterized by prolonged, persistent sadness associated with other symptoms such as anhedonia, lack of motivation, decreased self-care, variable sleep and/or appetite pattern, feelings of hopelessness, and/or suicidal thoughts. These symptoms may last for a couple of weeks to months (major depressive episode) or persist in a milder form for two or more years (dysthymia).

SSRIs are often considered first-line agents because of their benign side effect profile. Sertraline, citalopram, and escitalopram are often favored because of their limited drug-drug interaction. Most clinical trials have focused on sertraline, but results have been inconsistent. In a trial comprising 15 patients with mild TBI 87% had a significant response and 67% achieved remission with sertraline.3 In a follow-up study of patients with TBI-associated depression no significant differences were seen between sertraline and placebo in depression severity, response, or remission rates.4 Similarly, Ashman and colleagues5 found no statistically significant difference between sertraline and placebo in a group of 52 patients with TBI-associated depression. However, the small sample size (N=11) and the high rate of discontinuations may have contributed to the lack of difference between the medication and placebo groups.

SNRIs have also been used with fair success and no significant adverse effects, but they have not been systematically studied. In a small study (N=10) the tricyclic antidepressant (TCA) desipramine was shown to reduce depressive symptoms.6 However, because of anticholin- ergic adverse effects and risk for seizures, TCAs are less favored. Nortriptyline is considered to be the least anticholinergic and antihistaminergic among the TCAs and has demonstrated efficacy in the treatment of depression following stroke.7 However, we are not aware of controlled trials of nortriptyline in the treatment of TBI depression.

Monoamine oxidase inhibitors (MAOIs) may also be considered in persons with recalcitrant depression. However, the need for dietary restriction can be challenging because adherence to a strict diet may be difficult for patients with TBI who have cognitive deficits.

Salter and collegues8 conducted a systematic review and meta-analysis to determine the effectiveness of pharmacotherapy for the treatment of TBI depression and found a large, favorable treatment effect (Hedges g = 1.169; 95% CI, 0.849-1.489; P<.001) on pooled analysis of within-groups treatment effect. Even when the analysis focused on only placebo-controlled trials, treatment with antidepressants was associated with a statistically significant reduction in depressive symptoms.

Methylphenidate and other stimulants may be used to augment the effect of antidepressants, especially when there is evidence of fatigue, apathy, or executive function deficits. Lee and colleagues9 compared the efficacy of sertraline, methylphenidate, and placebo in a study of 30 patients with mild to moderate TBI. Both methylphenidate and sertraline significantly improved symptoms of depression, but only methylphenidate improved cognitive function. Patients treated with methylphenidate also had diminution in daytime sleepiness.

Electroconvulsive therapy (ECT) may be safe and effective in patients with TBI. Jorge and Arciniegas10 have suggested some common-sense approaches to using ECT in patients with TBI: use low energy levels to generate a seizure of about 20 seconds, use pulsatile currents, increase between-treatment time intervals to 2 to 5 days, and keep the number of treatments to a minimum. Non-dominant unilateral ECT has a decreased risk of cognitive adverse effects compared to bilateral ECT and may be preferable in TBI patients.

TBI-associated suicide. In a review of 48 studies, Simpson and Tate11 concluded that the risk of suicide, suicide attempts, and suicidal ideation is increased in TBI survivors compared with the general population, even after adjusting for psychiatric comorbidities. Mackelprang and colleagues12 also noted that 25% of their sample of 560 patients with all severities of TBI reported suicidal ideation during the first year following a TBI, a number much higher than 3.7% reported for the general population.

As in other cases of suicidal ideation, the most important factor in the management of TBI-associated suicide is to maintain safety. Immediate hospitalization should be considered for patients with active suicidal thoughts with intent or plan to die. Management of suicidal thoughts associated with psychiatric disturbances after TBI should focus on the psychiatric disturbances themselves. Extra caution to maximize safety is needed not only in the inpatient setting but also in the outpatient setting, ensuring that the patient has consistent outpatient care and a strong supportive network.

Post-TBI mania. The incidence of bipolar spectrum disorders is low in the TBI population, with a range of 2% to 9% in the first year after injury.2 Findings indicate the estimated lifetime relative risk for bipolar and related disorders to be 1.1, similar to the lifetime risk of bipolar disorders in the general population.13

TBI mania is characterized by changes in mood, sleep, and activation, which may manifest as irritability, euphoria, insomnia, agitation, aggression, impulsivity, or even violent behavior. There is scant literature on the pharmacological management of TBI mania.

Based on our clinical experience and case reports, we recommend use of quetiapine as a first-line and risperidone as a second-line agent for acute mania; we recommend valproate as first-line and carbamazepine as a second-line agent for maintenance. Although many psychopharmocologists might argue that lithium is the gold standard for the treatment of idiopathic bipolar disorder, we are concerned about the CNS and motor adverse effects in persons with TBI.

TBI-associated anxiety disorders. A wide range of anxiety disorders may occur after TBI including generalized anxiety disorder, agoraphobia, social phobia, panic disorder, and obsessive-compulsive disorder. Results from a meta-analysis of the prevalence of generalized anxiety disorder and self-reported anxiety in adults with non-penetrating TBI showed that 11% had a diagnosis of GAD, and 37% reported clinically significant levels of anxiety.

Commonly used medications for treatment of anxiety include sertraline, escitalopram, citalopram, and venlafaxine at doses similar to the treatment of TBI-associated depression.

PTSD. In a study of 1084 patients with mild TBI, 13% of the patients had PTSD.14 Higher incidence has been seen in military studies. Carlson and colleagues15 found that 64% of 836 veterans from Iraq/Afghanistan had PTSD. A recent review confirmed that PTSD occurs after TBI, but is more common after mild TBI.16 Although rates of TBI vary in the civilian population, they are higher in the military population, and the risk increases with the severity of TBI. The researchers concluded that the risk of PTSD varies according to the context in which the TBI occurred, the psychological trauma experienced at the time of TBI, and pre-TBI history of trauma or PTSD.

Sertraline is the first-line option for treating comorbid PTSD and TBI. Citalopram is a second choice, but caution is recommended above 40 mg daily because of potential cardiac adverse effects. Second-line agents include fluoxetine and mirtazapine, although the latter may be associated with mild anticholinergic adverse effects. SNRI antidepressants can also be used safely. Tricyclic antidepressants are third-line options. Prazosin may be used as adjunctive treatment for persistent nightmares. However, there were no statistically significant differences in sleep quality between prazosin and placebo in a recent 10-week study.17

Extreme caution should be used with benzodiazepines for treatment of anxiety disorders or PTSD. In general they should not prescribed for more than 2 weeks because longer use increases risk for dependence. TBI patients may have increased susceptibility to the adverse effects of benzodiazepines, including drowsiness, ataxia, slurred speech, memory impairment, psychomotor impairment, and possibly disinhibition. Moreover, benzodiazepines may aggravate the fear response in persons with PTSD.

TBI-associated psychosis. Psychotic symptoms are not uncommon after TBI. There are predominantly 2 types of TBI-related psychosis: delusional disorders and schizophrenia-like psychosis. As far as we know, there are no clinical medication trials on the management of TBI psychosis. Case reports suggest efficacy for second-generation antipsychotics.18 Based on our clinical experience, we recommend second-generation antipsychotics (risperidone, 0.25-4 mg; quetiapine, 25-200 mg; lurasidone, 20-80 mg) over first-generation antipsychotics because the latter may interfere with neural recovery in TBI. When there are concerns about the presence of seizures, anticonvulsants such as valproate or carbamazepine may be preferable.

Behavioral disturbances

Apathy. Apathy refers to a syndrome of disinterest, disengagement, inertia, lack of motivation, and absence of emotional responsivity. Although there are also emotional and cognitive aspects of apathy, we have chosen to include apathy under behavioral disturbance, as the disengagement and lack of involvement is most distressing for caregivers. Apathy can be a symptom of depression, which is the most common presentation, or occur as an isolated syndrome. As with most psychiatric disturbances in TBI, only reviews, anecdotal reports, and small case series are available to guide management. Most of the literature favors methylphenidate. Based on this and on our clinical experience, we recommend methylphenidate as a first-line agent.

Sleep disturbances. Sleep disturbances are common after TBI and can occur in isolation or as a symptom of a psychiatric disorder. Insomnia is the most common sleep disturbance, seen in about 50% of patients with TBI, although other disturbances such as hypersomnia, sleep apnea, and sleepwalking may also be present. Treatment of TBI sleep disturbance varies according to the type of sleep disorder and related comorbidities. Comprehensive medical evaluation including an overnight sleep study can help with the diagnosis of sleep disturbance. Maintenance of sleep hygiene is always first in the management of sleep disturbances. When sleep disturbance is comorbid with a psychiatric disorder, it is important to treat the underlying psychiatric disorder.

When insomnia occurs in isolation, consider use of a non-benzodiazepine hypnotic such as zolpidem for a short period. Other agents such as melatonin, amitriptyline, lorazepam, and zopiclone may also be considered. Benzodiazepines should be avoided secondary to risk for addiction, motor and cognitive adverse effects, and paradoxical rage outbursts. In patients with TBI who have excessive daytime sleepiness, sleep apnea should first be ruled out. Modafinil (100-400 mg) or armodafinil (150-300 mg) can be considered in patients with persistent and unexplainable daytime sleepiness.

Other behavioral disturbances. Other common behavior disturbances include impulsivity, aggression, and disinhibition. As with other psychiatric disturbances, management of post-TBI behavior problems should always be multifaceted. This includes a combination of environmental modification strategies, behavioral therapy, supportive therapy, family therapy, and pharmacotherapy. Medications should be based on presence of comorbid neuropsychiatric disturbances.

Cognitive deficits

The constellation of cognitive impairments following TBI is variable and depends on the severity of the location of the injury on the brain. TBI can affect every cognitive domain, including attention, memory, visual-spatial processing, language, social cognition, and executive functioning.

The core intervention for cognitive impairments is cognitive rehabilitation, which includes use of remediation techniques and external strategies to help individuals compensate for the deficits. In addition to cognitive rehabilitation, there are some pharmacologic options for augmenting cognitive functioning. The three main classes of pharmacological agents utilized to treat the cognitive sequelae of TBI are psychostimulants, cholinergics, and NMDA receptor antagonists.

Psychostimulants. Psychostimulant medications are commonly used to improve arousal/attention and related neurobehavioral symptoms after TBI. Methylphenidate is the first-line agent and most commonly used (5-40 mg/d). Methylphenidate may improve arousal, attention, and processing speed and general cognitive function in the subacute and chronic phase of injury. Lee and colleagues9 have also noted improvement in cognitive function and reduction in daytime sleepiness in addition to improvement in depression in persons with depression following TBI.

Cholinesterase inhibitors. Donepezil and rivastigmine have been studied for cholinergic augmentation following TBI. Donepezil is a centrally selective acetylcholinesterase inhibitor that has been may improve attention and memory during the subacute and chronic phase of injury and enhance sensory gating during the chronic TBI period. Rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase improved scores on the Hopkins Verbal Learning Test and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing mean latency, but only in patients with severe memory impairment at baseline.13

N-methyl-D-aspartate (NMDA) receptor antagonists. Amantadine and memantine are non-competitive antagonists at the NMDA receptor. They also enhance dopamine release, decrease presynaptic dopamine reuptake, stimulate dopamine receptors, and enhance postsynaptic dopamine receptor sensitivity. Amantadine was noted to help with arousal in the acute TBI period and with attention, visuospatial function, and executive functions in chronic TBI in persons with moderate to severe TBI.19 In our clinical experience, amantadine at dosages of 100-400 mg daily may be helpful for the treatment of executive dysfunction, more specifically for impulsivity, disinhibition, and poor motivation.

As far as we know, the efficacy of memantine on the psychiatric sequelae of TBI has not been studied. However, a recent prospective randomized trial in patients with moderate TBI revealed that patients in the memantine group compared with placebo had significantly reduced serum neuron-specific enolase levels by day 7 of injury, and improved Glasgow Coma Scale scores on day 3 of the study, underscoring its neuroprotective effect.20

Another approach is to use cognitive brain training. There are ongoing studies to see if intensive cognitive games can help in TBI. Elbogen and colleagues21 have studied a mobile cognitive training app (CALM) in TBI; they found that emotional regulation improved; however, executive functioning did not.

Conclusion

Psychiatric symptoms after TBI are common and troublesome. As TBI rates continue to remain high, there are many patients with long-term sequelae such as mood, behavioral, or cognitive symptoms.

Treatment of TBI symptoms is in line with treatment of symptoms in idiopathic psychiatric disorders; however, dosing may vary because of the potentially heightened sensitivity of the traumatized brain. There are also some medications used in TBI patients that are not used very often in general psychiatry, such as amantadine. (See Table for a summary of suggested agents to use in TBI.)

Unfortunately, there are limited studies for psychiatric symptoms after TBI; thus, there is a need for randomized, controlled trials. Hopefully, future treatment will be based on more rigorous group data but also with more personalized recommendations (based on biomarker or pharmacogenetic testing results). Optimal treatment may involve multimodal approaches, with pharmacotherapy, behavioral therapy, cognitive brain training, and neuromodulation.

Disclosures:

Dr Rao is Associate Professor, Department of Psychiatry and Behavioral Sciences and a member of the Miller Coulson Academy of Clinical Excellence, Johns Hopkins University, Baltimore, MD; Dr Vaishnavi is a Neuropsychiatrist, The Preston Robert Tisch Brain Tumor Center, Duke University. He is on the Faculty of Duke Institute for Brain Sciences, and Director, Transcranial Magnetic Stimulation and Director, Clinical Trials Carolina Partners, Durham, NC.

The authors report no conflicts of interest concerning the subject matter of this article.

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