Psychiatric Evaluation and Treatment Following TBI

Miss A R is a 56-year-old woman who survived a massive subdural hematoma last year after falling down the stairs. Despite an emergency craniectomy, the pressure inside her skull had been elevated for so long that she sustained severe injury to her brain tissue and remained in a coma for weeks. Neurologists never expected her to recover, but she gradually started to breathe on her own, and then to move, and then to talk, and so on. A R was heralded as a medical miracle, and appointments with various specialists swiftly fell into place concentrating on seizure prevention, physical rehabilitation, and treatment of a post-operative infection. However, during her first visit with her primary care doctor after discharge, the most urgent problem that A R wanted to address was a crippling depression unlike anything she had ever experienced before. She had survived her trauma and her family was ecstatic, but she wasn’t enjoying any part of the life that she had so fantastically regained. Feelings of guilt and loss predominated her thoughts. Furthermore, a sensation of bodily heaviness and a total lack of motivation had started to hamper her daily exercises. Despite getting 14 hours of sleep every night, she would rather stay in bed than go to her speech therapy appointments. Strange things were running through A R head; although she had never previously had a history of anxiety, she would spend entire weeks in bed ruminating on minor problems about the family car or the cell phone plan.

A R's personal struggle is reflective of a wider issue; depression and anxiety are prevalent in up to 50% of TBI patients, regardless of injury severity. Retrospective studies reveal that providers take an average of 40 days longer to initiate depression treatment for TBI patients compared to non-TBI patients.¹ This delay may seem insubstantial at first, but, considering the limited timeframe for neurological improvement in this patient population, time is invaluable. Mental health barriers are associated with impaired cognitive and physical recovery from TBI, so it is important to optimize psychiatric care for these patients.

Do traditional oral antidepressants such as SSRIs and SNRIs work in TBI patients?

Unfortunately, recent data has revealed that traditional oral antidepressants are no more effective than placebo in TBI patients.² Depression in TBI patients is different than primary depression in the general population. Neurobiological changes suggest a unique etiology comprising grey matter loss in the prefrontal cortex, neuroinflammation, and aberrant circuitry.³ These physical changes to the brain result in difficulty regulating emotions and further confound traditional pharmacological treatment.

So, should TBI patients just skip the antidepressants and proceed exclusively with psychotherapy?

This is a subject of contentious debate among psychiatrists. After researchers published the meta-analysis disproving the efficacy of antidepressants, neuropsychologists Noah Silverberg and William Pankenka fired back a response arguing that this new data should not change first line management with an SSRI.⁴ Perhaps the outcome measurements were flawed in primary studies (problems with sleep, appetite change, and psychomotor retardation are likely to disproportionately affect TBI patients), so why would we give up so easily? And let’s not underestimate the benefit of a robust placebo effect! Out of all the SSRIs, sertraline and citalopram have been studied the most in TBI patients, most likely due to tolerability. Therefore, we recommended prescribing either of those SSRIs or any medications that have proven personally efficacious for the patient in the past. However, tricyclic antidepressants should be avoided due to a low seizure threshold!³

How frustrating!! Modern medicine’s first line treatment for mood disorders in TBI patients *probably* doesn’t even work! Are these mood disorders permanent in TBI patients?

Although prevalence of anxiety and depression spike after the injury, they gradually decrease over time, most likely due to cortical healing.⁵ Although resolution of symptoms does not occur across the board, emphasis on the trend toward recovery can instill hope and spur progress in many patients. In Anna’s case, her newfound anxiety and depression improved 4 and 6 months after the injury respectively.

Prevalence of Mood Disorders in TBI Patients Over Time⁵

Based on the table above: Even before injury, TBI patients had a higher baseline rate of depression, anxiety, and substance abuse. Why is this?

These factors likely predispose many patients to traumatic injury through intoxication and reckless behavior.⁶ Therefore, it is imperative to refer any TBI patient with a history of substance abuse for addiction treatment to optimize healing and to prevent re-injury.

What about therapy for depression and anxiety?

As it stands, only a small portion of TBI patients receive psychotherapy in the year following their injury. Efficacy is controversial in TBI patients due to lack of high-quality studies, but psychotherapy have proven significantly beneficial for stoke patients, and similar principles likely stand for TBI patients. Cognitive based therapy (CBT) is the preferred form of therapy for reasons summarized nicely below in a 2013 systemic review⁷:  

“CBT techniques allow structured therapy sessions, which might be helpful for patients with deficits in executive functioning. For patients who have memory impairment, CBT provides possibilities to repeat important information. Moreover, through CBT techniques, patients perceive a sense of control, which seems to be essential for this population in particular.”

If antidepressants and psychotherapy fail to improve the patient’s mood over a duration of several months, what is the next step?

First and foremost, clinicians may consider a trial of a second antidepressant, but this is controversial for reasons described above. Otherwise, transcranial magnetic stimulation was FDA approved for the treatment of primary depression in 2008, and three clinical trials have already shown efficacy in TBI patients.³ TMS is a form of noninvasive brain stimulation that pushes a magnetic field through the prefrontal cortex (remember, that’s the part of the brain involved in emotional regulation). Patients demonstrated an average of 56% improvement in depression scores after 20 treatments⁸, including individuals who had failed to respond to pharmacological antidepressants in the first place. One pilot study also demonstrated an improvement in cognition in TBI patients⁹.

TMS and intranasal ketamine (Spravato) are often grouped together in discussions about treatment resistant depression. Can TBI patients treat depression symptoms with ketamine?

Intranasal ketamine has not yet been studied in the context of TBI patients. Theoretically, ketamine should work very well in TBI patients based on studies showing anti-inflammatory and neuroprotective effects in mice.¹⁰ Researchers have been reluctant to extend these trials to humans due to a previous misconception that ketamine can increase intracranial pressure (something we want to avoid in TBI patients), but this theory has been debunked in recent years. Stay tuned for future research – it could be very promising!

Patients have a an extremely high incidence of sleep-wake disorders following a TBI. How do these changes present?

Sleep-wake disorders can manifest as excessive daytime sleepiness, increased sleep requirement (often exceeding 12 hours per day), and problems with sleep onset or sleep maintenance insomnia. Less commonly, TBI patients may exhibit complex sleep behaviors such as sleep walking, sleep driving, and using the stove while asleep.

Daytime sleepiness is the most common sleep complaint reported by TBI patients and is especially problematic as it may have detrimental effects on motivation for rehabilitation. Are there any options to treat this?

Before treating, it is important to evaluate for contributing factors to fatigue such as depression, chronic pain, or medication side effects. Once these are addressed, patients can try off-label use of modafinil (Provigil) or armodafinil (Nuvigil) to improve alertness during the day. These medications were originally approved to treat narcolepsy, but a few clinical trials have demonstrated utility in treating TBI patients as well. Methylphenidate (Ritalin, Concerta) is another option to treat these symptoms, but it is not as well studied in this population.¹¹

What about insomnia?

Benzodiazepines and sedative hypnotics are equally effective in treating insomnia following a TBI. However, the lowest effective dose should be prescribed due to the addictive potential of these medications, especially since many patients TBI patient possess an underlying history of substance abuse. Unfortunately, studies have shown that the safe over-the-counter medication melatonin does not effectively treat TBI-related insomnia.¹¹

TBI patients tend to sleep at least 12 hours at a time; should they be woken up to conform to their previous sleep habits?

No. This increased sleep time may represent a physiological requirement. Patients should be permitted to sleep longer than most individuals in case the extra sleep cycles promote cortical healing.¹¹

References

1. Albrecht JS, Abariga SA, dosReis S, Perfetto EM, Mullins CD, Rao V. Receipt of Treatment for Depression Following Traumatic Brain Injury. J Head Trauma Rehabil. Sep/Oct 2020;35(5):E429-e435. doi:10.1097/htr.0000000000000558
2. Kreitzer N, Ancona R, McCullumsmith C, et al. The Effect of Antidepressants on Depression After Traumatic Brain Injury: A Meta-analysis. J Head Trauma Rehabil. May/Jun 2019;34(3):E47-e54. doi:10.1097/htr.0000000000000439
3. Liu Q, Li R, Qu W, Li B, Yang W, Cui R. Pharmacological and non-pharmacological interventions of depression after traumatic brain injury: A systematic review. Eur J Pharmacol. Dec 15 2019;865:172775. doi:10.1016/j.ejphar.2019.172775
4. Silverberg ND, Panenka WJ. Antidepressants for depression after concussion and traumatic brain injury are still best practice. BMC Psychiatry. Mar 27 2019;19(1):100. doi:10.1186/s12888-019-2076-9
5. Ashman TA, Spielman LA, Hibbard MR, Silver JM, Chandna T, Gordon WA. Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders. Arch Phys Med Rehabil. Apr 2004;85(4 Suppl 2):S36-42. doi:10.1016/j.apmr.2003.08.117
6. Koponen S, Taiminen T, Hiekkanen H, Tenovuo O. Axis I and II psychiatric disorders in patients with traumatic brain injury: a 12-month follow-up study. Brain Inj. 2011;25(11):1029-34. doi:10.3109/02699052.2011.607783
7. Stalder-Lüthy F, Messerli-Bürgy N, Hofer H, Frischknecht E, Znoj H, Barth J. Effect of psychological interventions on depressive symptoms in long-term rehabilitation after an acquired brain injury: a systematic review and meta-analysis. Arch Phys Med Rehabil. Jul 2013;94(7):1386-97. doi:10.1016/j.apmr.2013.02.013
8. Siddiqi SH, Trapp NT, Hacker CD, et al. Repetitive Transcranial Magnetic Stimulation with Resting-State Network Targeting for Treatment-Resistant Depression in Traumatic Brain Injury: A Randomized, Controlled, Double-Blinded Pilot Study. J Neurotrauma. Apr 15 2019;36(8):1361-1374. doi:10.1089/neu.2018.5889
9. Lee SA, Kim MK. Effect of Low Frequency Repetitive Transcranial Magnetic Stimulation on Depression and Cognition of Patients with Traumatic Brain Injury: A Randomized Controlled Trial. Med Sci Monit. Dec 4 2018;24:8789-8794. doi:10.12659/msm.911385
10. Liang J, Wu S, Xie W, He H. Ketamine ameliorates oxidative stress-induced apoptosis in experimental traumatic brain injury via the Nrf2 pathway. Drug Des Devel Ther. 2018;12:845-853. doi:10.2147/dddt.s160046
11. Lim MM, Baumann CR. Sleep-wake disorders in patients with traumatic brain injury. UpToDate2021.