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Agitated and depressed with a traumatic brain injury

Current Psychiatry. 2023 September;22(9):44-48 | doi: 10.12788/cp.0390

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, text revision. American Psychiatric Association; 2022.

2. Serra F, Gordon‐Smith K, Perry A, et al. Agitated depression in bipolar disorder. Bipolar Disord. 2019;21(6):547-555. doi:10.1111/bdi.12778

3. Meresh E, Daniels D, Owens JH, et al. Psychotropics and neuroprotection: literature review and case series report. OBM Neurobiol. 2020;4(1). doi:10.21926/obm.neurobiol.2001048

4. Williamson DR, Frenette AJ, Burry L, et al. Pharmacological interventions for agitation in patients with traumatic brain injury: protocol for a systematic review and meta-analysis. Syst Rev. 2016;5(1):193. doi:10.1186/s13643-016-0374-6

5. DeBattista C, Solomon A, Arnow B, et al. The efficacy of divalproex sodium in the treatment of agitation associated with major depression. J Clin Psychopharmacol. 2005;25(5):476-479. doi:10.1097/01.jcp.0000177552.21338.b0

6. Longo LP, Campbell T, Hubatch, S. Divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. J Addict Dis. 2002;21(2):55-64. doi:10.1300/J069v21n02_05

7. Sher Y, Cramer ACM, Ament A, et al. Valproic acid for treatment of hyperactive or mixed delirium: rationale and literature review. Psychosomatics. 2015;56(6):615-625. doi:10.1016/j.psym.2015.09.008

To treat agitation associated with MDD, second-generation antipsychotics and valproic acid have shown significant neuroprotective effects. The proposed mechanisms for neuroprotection include not only antioxidant effects but 5HT1A agonist properties, with the latter thought to protect against excitotoxic injury that may exacerbate agitation due to brain trauma.³

There is no consensus on which antipsychotics are most efficacious for treating agitation in the setting of an acute TBI. Williamson et al⁴ reviewed various medications that may treat agitation in the setting of acute TBI with fewer adverse effects.

Though haloperidol is often prescribed to treat agitation in patients with TBI, animal studies have shown it is inferior to second-generation antipsychotics in protecting against excitotoxic/oxidative injury, and haloperidol has been associated with neuronal loss. Haloperidol has been linked to adverse clinical outcomes for patients with aggression after TBI, including prolonged amnesia, which is thought to be linked to haloperidol’s strong and selective dopamine-2 receptor antagonism and the mesocortical and nigrostriatal pathways involved.⁴

Carbamazepine, phenytoin, and methylphenidate cause oxidative stress and/or apoptosis, and therefore offer no neuroprotection. Data on gabapentin are mixed; a few studies suggest it may block synapse formation or decrease quantities of antioxidant enzymes in the brain, though it’s known to protect against glutamate-induced neuronal injury.³

Additional research is needed to assess which second-generation antipsychotics offer the most neuroprotection. However, based on existing literature, olanzapine and aripiprazole may offer the most benefit because they have the greatest antioxidant—and thus, neuroprotective—activity. Cognitive enhancers such as memantine and donepezil exhibit neuroprotection, particularly in Alzheimer disease. Anticonvulsants such as levetiracetam, lacosamide, and lamotrigine offer neuroprotection and may be considered for seizure prevention.³ The Table³^-6 lists psychotropic medications used to treat TBI.

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Agitated and depressed with a traumatic brain injury

References

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