Modifying Psychopharmacologic 

Interventions for Traumatic Brain Injury 

BRIEF | January 2023 

Introduction & General Approach 

Introduction 

Alterations of mood, cognition, and behavior are 

common after a Traumatic Brain Injury (TBI) and 

are best understood in the context of a 

biopsychosocial model. Disruption of key brain 

circuitry, pre-injury personality traits, and family, 

sociocultural, economic, and other medical factors 

each play roles in determining an individual’s 

unique symptoms. 

Ideal treatment of posttraumatic neuropsychiatric 

symptoms involves a comprehensive, multipronged 

approach tailored to specific cognitive, emotional 

and social needs. Psychopharmacologic treatment, 

often a crucial component of treatment, is most 

effective when delivered in tandem with nonpharmacologic supportive strategies. 

The goal of this brief is to provide state brain injury 

personnel with information to communicate with 

their behavioral health partners, providing them with 

an array of accessible approaches for modifying 

psychopharmacologic interventions for TBI. 

General approach 

Psychiatrists already possess the fundamental 

clinical evaluation skills needed to evaluate and 

treat posttraumatic neuropsychiatric symptoms 

effectively. Psychiatrists should feel empowered to 

adapt existing skill sets to meet the complex—but 

often highly treatment-responsive—needs of 

individuals with brain injury. 

While symptom interpretation in TBI can be 

challenging and the evidence base for most 

interventions is relatively limited, pharmacotherapy 

can be a crucial component of treatment. 

Adherence to a systematic approach that 

emphasizes identification of specific psychiatric, 

cognitive, and behavioral target symptoms is key. 

These target symptoms can then be used to 

develop working diagnoses and guide rational 

pharmacotherapy. Pharmacotherapy approaches 

may be extrapolated from data related to the 

primary psychiatric disorder an individual’s 

symptoms most resemble or informed by studies 

specific to TBI, if available. 

Medication selection may also be driven by a 

hypothesis of the neurotransmitter disturbances 

involved based on the extent and location of 

structural brain injury. Because symptoms can 

change over time, especially early in the recovery 

course, ongoing monitoring for treatment response 

and adverse effects is essential. 

Psychiatric Assessment: 

Modifications for TBI 

Assessment begins with the standard 

initial psychiatric evaluation and is supplemented 

with additional history and examination geared 

toward identifying common neurocognitive and 

neurobehavioral sequelae of TBI that may 

confound psychiatric diagnosis and/or represent 

independently treatable target symptoms. 

Please note that timing of assessment is 

particularly critical due to the nature of the TBI 

recovery process, with dramatic neurobehavioral 

changes expected in the first days, weeks and 

months following TBI. 
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Psychiatric interview 

Cognitive impairments, especially related to selfawareness and verbal communication, may make it 

difficult for individuals with TBI to report symptoms 

accurately. Collateral information from a reliable 

family member or other caregiver is crucial. 

In addition to the inquiries about mood, anxiety, 

psychosis, and other psychiatric symptoms, these 

domains warrant special attention in TBI: disorders 

of sleep and wakefulness; emotional and 

behavioral dyscontrol1

; disorders of diminished 

motivation2

; agitation3; and neurocognitive 

symptoms. 

Medical & Neurological 

Review of Systems 

Medical complications of TBI can contribute to 

neuropsychiatric symptoms, and the presence of 

neuropsychiatric symptoms may interfere with the 

injured individual’s ability to seek out and 

participate appropriately in necessary medical care. 

Neurological symptoms 

Common issues include, but are not limited to: 

•	 Headaches 

•	 Visual disturbances and eye movement 

abnormalities 

•	 Vestibular system dysfunction 

•	 Seizures 

•	 Dysautonomia 

•	 Spasticity 

•	 Chronic pain 

•	 Neuroendocrine dysfunction 

•	 Nausea and vomiting 

•	 Bowel and bladder dysfunction 

•	 Musculoskeletal pain 

A full review should also include: 

•	 Comprehensive details of injury 

•	 Thorough pre- and post- injury functioning: 

personal and family 

•	 Psychiatric history, substance use, medical, 

social and occupational history 

Examination & Further Assessment 

In addition to the psychiatric mental status exam, 

basic cognitive function should be evaluated with 

particular emphasis on attention, memory, 

language, and executive function. 

Further neurological and medical assessment 

should be considered on a case-by-case basis. 

Neuroimaging in particular may be beneficial in 

demonstrating extent of injury to neural circuitry 

crucial for regulation of mood and behavior 

(especially in the frontal and temporal lobes). 
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Psychopharmacologic Treatment: General Principles in TBI 

While identification of clear target symptoms is essential to good psychopharmacologic practice in any 

population, it is of the utmost importance in TBI, where the organizational structure provided by a diagnosis 

may not be readily available. 

Absence of a clear, definitive psychiatric diagnosis need not preclude attempts at pharmacologic treatment as 

long as there is a solid rationale linking medication choice with target symptoms. 

General Psychopharmacological Treatment Principles 

Whenever Possible, Add by Subtraction First 

Before adding a new medication, consider whether reduction or removal of any medications might benefit target 

symptoms. 

“Start Low, Go Slow — but Go.” 

Individuals with TBI are sensitive to adverse effects of psychotropic medications. Initiation of any pharmacotherapy should 

begin with a low starting dose and be titrated gradually. 

Reassess Frequently and Adjust as Needed 

The target symptoms, treatment response, and presence of side effects must be reassessed frequently, with therapy 

adjusted accordingly. 

Avoid Polypharmacy — Most of the Time 

All efforts should be made to streamline medication regimens, but in some cases dose reduction in conjunction with 

addition of a low dose of a second synergistic agent may prove beneficial. 
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Specific Posttraumatic Neuropsychiatric Syndromes 

Agitation 

First-line management: 

• Reduce external stimuli by minimizing light, noise and other distractions. 

• Minimize use of restraints, tubes and lines. 

• Staff and patient family members should frequently reorient the patient. 

• Encourage proper sleep hygiene and sleep quality with a sleep schedule and bedtime routine and minimize use 

of electronics 30–60 minutes before bedtime. 

• For restless patients, supervised ambulation may be helpful. 

• Patients with aggression or behavioral issues should be managed by staff trained in de-escalation techniques. 

Pharmacological Management: 

• Use of beta blockers (propranolol), antiepileptic drugs (carbamazepine, valproic acid), antidepressants 

(selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, trazodone, lithium), antipsychotics 

(typical and atypical), neurostimulants (amantadine, methylphenidate) and anxiolytics (buspirone, 

benzodiazepines).

4,5 

• Medications should be trialed one at a time, in the lowest starting dose available and with slow increases, while 

monitoring for medication effectiveness and side effects. Frequent reassessment is critical. 

• Be mindful that the effective dose for medications commonly used in the general population may be lower in 

the brain injury population due to the sensitivity of the brain after injury (although traditional therapeutic doses 

may ultimately be necessary). Furthermore, the need for medication and medication dosing may change during 

the course of brain injury recovery. 

• Propranolol has the best evidence for efficacy in treating agitation in the brain injury population with no adverse 

effect on motor or cognitive recovery. It has been shown to improve restlessness, disinhibition, anxiety, and 

tremor. Consider a starting dose of 10 mg given three to four times a day with a maximum dose of 240 mg/day. 

Side effects include hypotension, bradycardia and lethargy. Propranolol should be considered a maintenance 

medication, to be given around the clock, and not on an as-needed basis for periods of acute agitation. 

• For acute agitation, consider atypical antipsychotics such as quetiapine, ziprasidone, and olanzapine, again with 

low starting doses and given as needed. Side effects include sedation, extrapyramidal symptoms and dizziness. 

It is recommended to avoid use of typical antipsychotics (haloperidol) and benzodiazepines as they may hinder 

long-term motor and cognitive recovery, prolonged posttraumatic amnesia, and have risk of dependence and 

addiction. 

Sleep dysfunction 

Pharmacological Management: 

•	 Use of melatonin and melatonin agonists (ramelteon), trazodone and mirtazapine. 

•	 Medications should be trialed one at a time, in the lowest starting dose available, with slow increases, while 

monitoring for medication effectiveness and side effects. Frequent reassessment is critical. 

•	 Use caution in older adults with all sedating medications, which may increase risk of nighttime falls. 

•	 Other options used include tricyclic antidepressants (which may concurrently treat neuropathic pain and 

insomnia) and hypnotics (e.g., zolpidem, zopiclone, eszopiclone, zaleplon). 

•	 Neurostimulant use for daytime arousal may facilitate nighttime sleepiness and improve sleep dysfunction. 

Stimulants for daytime wakefulness should typically be trialed only after attempts have been made to 

consolidate nighttime sleep. Modafinil, a wakefulness-promoting agent approved for the treatment of narcolepsy 

and excessive daytime sleepiness due to obstructive sleep apnea, may be of use. 

•	 Non-pharmacologic interventions may also be beneficial, including bright light therapy, cognitive behavioral 

therapy, stimulus control, and cognitive restructuring. 
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Disorders of affect, mood, and anxiety 

Pharmacological Management — Posttraumatic Affective Dysregulation: 

•	 SSRIs are the first-line treatment for posttraumatic affective dysregulation and can be highly effective for this 

problem, typically at lower doses than are required for treatment of depression and with therapeutic benefit 

often seen within days of drug initiation. 

•	 Tricyclic antidepressants (TCAs) can also be useful, though their greater side effect profile warrants some 

additional caution. 

•	 Nuedexta, a combination drug comprised of dextromethorphan and quinidine, is approved for the treatment of 

pseudobulbar affect (pathologic laughing and crying) and can be tried if SSRIs and TCAs are unsuccessful or 

contraindicated. 

Pharmacological Management — Posttraumatic Depression: 

•	 SSRIs such as sertraline and fluoxetine.6 

•	 Serotonin-norepinephrine reuptake inhibitors (SNRIs) and TCAs. 

•	 Because these medications are also effective for pain, SNRIs and TCAs may be of particular utility when there 

are co-occurring headaches or other pain syndromes. Medications should be trialed one at a time, in the lowest 

starting dose available, with slow increases while monitoring for medication effectiveness and side effects. 

•	 Cognitive behavioral therapy, problem-solving therapy, and behavioral activation training have shown favorable 

outcomes for treating depression in the brain injury population. 

Neurocognitive Impairments 

Pharmacological Management: 

The most commonly used medications are amantadine, a glutamate antagonist with dopamine-modulating properties 

approved for treatment of Parkinson’s disease and drug-induced parkinsonism; ethylphenidate, a stimulant approved for 

treatment of ADHD; and donepezil, an acetylcholinesterase inhibitor approved for treatment of Alzheimer’s disease. 
Modifying Psychopharmacologic Interventions Page | 6 

Source 

Content for this brief was drawn from Section VI. Psychopharmacologic Interventions for TBI, of the 

Administration for Community Living. 2022. Behavioral Health Guide: Considerations for Best 

Practices for Children, Youth, and Adults with TBI available at: 

https://acl.gov/sites/default/files/programs/2022-05/TBITARC_BH_Guide_Final_May2022_Accessible.pdf. 

The section was written by Michael Chiou, MD, and Lindsey Gurin, MD, NYU Langone Health. The 

Traumatic Brain Injury Technical Assistance and Resource Center is funded by the Administration for 

Community Living. The Human Services Research Institute and the National Association of State 

Head Injury Administrators administer it. 

For more information, visit https://acl.gov/programs/post-injury-support/traumatic-brain-injury-tbi. 

References 

1 Castano Monsalve, B., Laxe, S., Bernabeu Guitart, M., Vilarrasa, A. B., & Quemada, J. I. (2014). 

Behavioral scales used in severe and moderate traumatic brain injury. NeuroRehabilitation, 

35(1),67–76. https://doi.org/10.3233/NRE-141103 

2 Bhatnagar, S., Iaccarino, M.A., & Zafonte, R. (2016, June 1). Pharmacotherapy in rehabilitation of 

post-acute traumatic brain injury. Brain Research,1640(Pt A),164–179. 

https://doi.org/10.1016/j.brainres.2016.01.021 

3 Castano Monsalve, B., Laxe, S., Bernabeu Guitart, M., Vilarrasa, A. B., & Quemada, J. I. (2014). 

Behavioral scales used in severe and moderate traumatic brain injury. NeuroRehabilitation, 

35(1),67–76. https://doi.org/10.3233/NRE-141103 

4 Luaue, J., Plantier, D., Wiart, L., Tell, L., SOFMER group. (2016, February) Care management of the 

agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and 

practice recommendations. Ann Phys Rehabil Med, 59(1), 58-67. 

https://doi.org/10.1016/j.rehab.2015.11.001 

5 Bhatnagar, S., Iaccarino, M.A., & Zafonte, R. (2016, June). Pharmacotherapy in rehabilitation of postacute traumatic brain injury. Brain Research, 1640(Part A),164-179. 

https://doi.org/10.1016/j.brainres.2016.01.021 

6 Fann, J.R., Hart, T., & Schomer, K.G. (2009, December). Treatment for depression after 

traumatic brain injury: a systematic review. Journal of Neurotrauma, 26(12), 2383-402. 

https://doi.org/10.1089/neu.2009.1091