Addressing Disinhibition and Cognitive Problems

Research on Neuroprotective Agents in TBI

Traumatic Brain Injury: An Interview with Jonathan Silver

Unfortunately, lots of people get blows to the head. But how do you know when the brain is injured? And what do you do about it? Welcome to the Carlott Psychiatry Podcast, keeping psychiatry honest since 2003. 

I'm Chris Akin, the editor-in-chief of the Carlott Psychiatry Report. 

And I'm Kelly Newsom, a psychiatric NP and a dedicated reader of every issue. 

A traumatic brain injury, or TBI, is not the same as a head injury. We're talking here about an injury to the brain, not the face or the ears. And we're talking about a traumatic injury, not a stroke or a tumor. 

All people kind of agree on what you need to define a traumatic brain injury. And so first, it's caused by the application of force to the brain, which immediately differentiates it from other acquired brain injuries, such as a stroke, such as an anoxic brain injury from a cardiac arrest. 

The brain is protected by a hard skull, but there's little to protect it within that skull. And much of the trauma in TBI comes from the sudden movement of the brain within the skull. Additional or secondary injuries can happen after the trauma through changes in cerebral blood flow or intracranial pressure. The resulting structural damage is not always detectable on CT and MRI, but it does show up in symptoms, including cognitive problems, depression, apathy, irritability, headaches, sleep problems, just about everything we see in psychiatry. One of the first treatments for traumatic brain injury was opening the skull to relieve the intracranial pressure in the early 19th century. Going back further, it was probably because of brain injuries that the ancient Greek physicians like Apocrates understood the brain to be the center of thought. 

Common causes of TBI are falls, motor vehicle accidents, and violence. While older adults are more prone to falls, TBI is most common in children and young adults. Look forward in patients with PTSD. There's increasing awareness that victims of domestic violence and child abuse have higher rates of TBI. Last year's researchers at Ohio State University looked at rates of head injury, not brain, but head, in women who had sought help for domestic violence. 81% had suffered blows to the head, and 83% had been strangled. 

Not all head injuries are brain injuries, and not all strangulations cause enough hypoxia to damage brain tissue. But it's important not to miss these cases whose problems with memory, mood, and irritability might otherwise be ascribed to PTSD. Another population to look out for is the homeless. A 2019 study found that half of homeless people have suffered a TBI. In this month's report, we featured an interview with Jonathan Silver on TBI, and today we'll share a few highlights and rare outtakes from that conversation. What is a TBI? 

Traumatic brain injury specifically refers to those people who had a brain injury due to the application of force. And the definition is at the time of that application of force, there's some evidence of an alteration in brain function. In the most severe cases, it could be a period of coma, which is the person's not arousable. It could be a period of post-traumatic amnesia, where people don't remember things for a period of time before or after the injury. Or it could be feeling dazed, confused, seeing stars, which is even more common in the sport's less severe types of injury. 

How is a TBI different from a concussion? What I and many of my 

colleagues use for concussion is the mildest form of mild traumatic brain injury. Those are people who have briefed or no loss of consciousness and brief periods of post-traumatic amnesia. Most often, due to sports. So that is how I use the term concussion. You'll see research studies using concussion as a synonym for mild traumatic brain injury, which means that somebody could be unconscious for 25 minutes and they'll still call it a concussion. I don't call it a concussion. 

Where do you start with treatment for TBI? 

First, patients often have more than one symptom. The question is, what do you start with? So it's very common that people have problems with sleep, concentration, depression. Do you start with an antidepressant? Do you start with sleep? Do you start with something for their concentration and attention? I think the first thing you'd probably target is sleep, because if your sleep isn't good, it makes your cognition worse. 

It makes your mood worse. It's like, what medication would you think of for somebody who has trouble sleeping and maybe they're depressed? I mean, we often use tracidone because of sedating properties. You could try Remeron, which is a nice sedating antidepressant. I think theoretically we try to stay away from benzodiazepines just because they're not great for memory. They're not great for balance or other issues. I can't say I don't use them, but it would be something that we probably don't start with. 

I know that benzos can cause disinhibition, much like alcohol can. Do we see more disinhibition with benzos in the TBI population? 

It's interesting. It's like case for pain. It's really rare. It's written about a lot, but it doesn't happen that often. There's a lot that's written about frequently, and I probably am one of the people that have done that, but it's not that common. 

So disinhibition is rare. Are you more concerned here with benzos about cognitive problems and imbalance in TBI? 

Right. I mean, we know benzodiazepines in pair memory. They're great anti-anxiety medicines. So it'd be something that I would try not to use first. 

What do you start with for irritability in TBI? 

For irritability and aggression, that's a big problem with people with traumatic brain injury of all severities. Actually, one of the first medications I use is Puse Perum, which really is very helpful for lots of patients with irritability after traumatic brain injury. 

That is really well tolerated. There's almost no downside to trying it. If you don't feel lightheaded about a half hour, 45 minutes after you take it, there's no weight gain. There's no sexual side effects. There's no drug interactions. It really works for it. For some people, it works very well. 

I start with 7.5 milligrams twice a day, and after one week, I go to 15 milligrams twice a day. After a couple of weeks, if there's no change, I usually give up. Some people push the dose. If there's some benefit, I could push the dose up to 30 twice a day. I remember somebody in meetings say they give like 60 twice a day, but I've not done that. 

Amantadine was once called the best study drug for irritability in TBI, but I understand the more recent data doesn't look so good. Can you update us on that? 

The two best studies in irritability after traumatic brain injury were both done by Thorhamon. The first one when she was at Carolinas, and the other University of Indiana when she was head of the Multicenter study. 

And that's the one that I was head of this data safety monitoring board was the Multicenter. study. The first study, which was a single center study, showed a significant improvement in patients on a mannedin compared to placebo. 

Wonderfully done study with on a 15. I had a lot of patients. Very large single center study. 

It was very impressive. Now the second study was also impressive, and I forgot whether I had 120 or 130 patients, and there was no difference between groups. There was no difference between the people on a mannedin and the people on placebo. And the issue is everyone got better. It's not like the people on a mannedin didn't get better, the people on the placebo didn't get better. 

Everybody responded. They designed the study in such a way that the placebo group had such a therapeutic interaction with support and all the staff that everyone got better. So it was a negative study in terms of efficacy of a mannedin. 

So what do you do with that? You could say it shows it didn't work, or you could say I don't believe it works, or it worked, but you can't tell the difference between that and placebo. There are different interpretations, but that study did not show a beneficial effect of a mannedin on the primary predetermined efficacy measure. 

Period. I could say clinically it's not been the most potent medication for my patients, maybe some, but it's certainly something worth considering. There's enough evidence to say this is something that's worth trying. 

I start with 100 milligrams once a day and after a week, 100 twice a day, morning and like mid-afternoon. 

Yeah, I have. If there's nothing on 200, I usually stop, but there's something on 200, maybe I'll go to 300. 

How do you address memory problems in this population? 

So for memory, we spoke about cognition in general, the psychostimulants may help with attention and concentration. For memory, there's very good class one evidence, the acetylcholinesterase inhibitors can improve memory in people with significant memory deficits after traumatic brain injury. And I was principal investigator on the remistiginine study and there are a couple of denepezil studies where there can be significant clinical improvement. Your memory doesn't get a whole better for patients to notice a difference. 

Patients with significant memory complaints, especially if you see this on testing, deserve a trial. I usually use denepezil, start with five milligrams for the first month and they're going to 10 milligrams. They don't notice anything after two months and I stop. But I believe patients need a trial on one of the colonase-traised inhibitors. I mean rivastigmine comes as a patch, so you can use that if patients have trouble with pills or there's some side effect problems with denepezil, but they deserve a trial with some colonase-traised inhibitor. 

There are things we try but I'm not very optimistic on how well they work. Apathy is a big problem for the family, not for the patient because they just don't care. They don't mind that they're not doing anything and it drives the family crazy. They just can't take the fact that their relative is not motivated. Thank you Dr. Silver. 

Jonathan Silver is a clinical professor of psychiatry at New York University School of Medicine and co-editor of the textbook of traumatic brain injury which is in its third edition from APA Press. Check out the full interview online which includes tips on lifestyle approaches to TBI and how to address depression, irritability and memory as well as medication side effects in this population. 

And as usual we have a handy table, this one with eight medications for cognitive symptoms in TBI and how to dose them. And now for the word of the day, neuroprotection. 

Many things can injure the brain, ischemia, toxic chemicals, seizures, infection and blunt force. Neuroprotective agents are those that preserve neuronal structure and function in the face of these neurotoxic injuries. There are many ways to achieve this effect such as raising growth factors like brain-derived neurotrophic factor or BDNF or raising neuroprotective factors like BCL2 or reducing inflammation or toxic compounds that build up like glutamate or just preventing cell death or apoptosis. Most psychiatric medications and many vitamins and supplements we use in psychiatry are neuroprotective. Some though, like the atypical antipsychotics, have both neuroprotective and neurotoxic effects. 

That explains TARDIF dyskinesia. While others like the psychostimulants, the traditional ones, methylphenidate and amphetamine, and the benzos, don't offer any real protection and can be neurotoxic in high doses. Among psychmeds, lithium has the strongest neuroprotective properties which occur through multiple mechanisms throughout the entire brain, whereas antidepressants offer more limited neuroprotection in the area of the hippocampus and amygdala. Still, that's enough that outcomes are better when someone has a stroke while taking an SSRI versus not, independent of whether they develop depressive symptoms. So what do lithium's neuroprotective mechanisms mean? They might explain why lithium prevents dementia as well as mood relapses. But what about in TBI? 

There we don't know. Many neuroprotective agents have been tested in TBI and so far they tend to work in animal studies, but don't pan out in human studies. Dr. Silver speculated that this might have something to do with timing. 

Now the animal models, you're giving it either before the injury or like right after the injury. Kind of hard for people, for EMS to give it. So is it that it's given a little too late or it doesn't work? 

Lithium has never been tested in controlled studies of humans with TBI, but in animal studies of TBI, lithium reduces neuronal death, reduces amyloid and tau buildup, that's the stuff that can cause dementia, and preserves the integrity of the blood-brain barrier. But think twice before you jump in with lithium in TBI. These patients are more sensitive to the neurologic side effects of lithium, like tremor and cognitive problems. On the other hand, TBI is itself a risk factor for dementia and very low doses of lithium, like 300 micrograms, that's 0.3 milligrams, you'd have to get that in a liquid form, or up to 150 milligrams a day. So very low doses prevent dementia. So we'd like to see a study of microdose lithium in TBI. 

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Traumatic Brain Injury: An Interview with Jonathan Silver

from The Carlat Psychiatry Podcast

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Derek Harmanli

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Traumatic Brain Injury: An Interview with Jonathan Silver

from The Carlat Psychiatry Podcast

Media

Links

Key Points

Summary

Transcript

Disclaimer and Important Information

Derek Harmanli

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Related Posts

Categories